High Altitude Medicine

and Physiology

The authors, with two other colleagues, outside the Silver Hut at 5800 m in the Everest region
during the Himalayan Scientific and Mountaineering Expedition, 1960-1961. Left to right:
Dr.J.S. Milledge, Professor J.B. West, Dr. LG.C.E. Pugh, Dr. M.P. Ward and Dr. M.B. Gill.

High Altitude Medicine and

Physiology
3rd Edition
by

Michael P Ward CBE, MD, FRCS

Past Master, Society of Apothecaries of London, formerly Consultant Surgeon and Lecturer in Clinical
Surgery, London Hospital Medical College, London, UK

James S Milledge MD, FRCP

Formerly Consultant Respiratory Physician and Medical Director, Northwick Park Hospital, Harrow, UK

John B West MD, PHD, DSC, FRCP, FRACP

Professor of Medicine and Physiology, the School of Medicine, University of California, San Diego, USA

A member of the Hodder Headline Group

LONDON
Co-published in the USA by
Oxford University Press Inc., New York

First published in Great Britain in 2000 by

Arnold, a member of the Hodder Headline Group,
338 Euston Road, London NW1 3BH
http://www.arnoldpublishers.com
Co-published in the USA by
Oxford University Press Inc.,
198 Madison Avenue, New York NY10016
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2000 Arnold
All rights reserved. No part of this publication may be reproduced or
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are issued by the Copyright Licensing Agency: 90 Tottenham Court Road,
London W1POLP.
Whilst the advice and information in this book are believed to be true and
accurate at the date of going to press, neither the author[s] nor the publisher
can accept any legal responsibility or liability for any errors or omissions
that may be made. In particular (but without limiting the generality of the
preceding disclaimer) every effort has been made to check drug dosages;
however, it is still possible that errors have been missed. Furthermore,
dosage schedules are constantly being revised and new side-effects
recognized. For these reasons the reader is strongly urged to consult the
drug companies' printed instructions before administering any of the drugs
recommended in this book.
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
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ISBN 0 340 75980 1 (hb)
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Printed and bound in Great Britain by Bath Press, Bath

Contents

Preface

vii

Acknowledgments

ix

Conversion tables

xi

List of abbreviations

xiii

History

The atmosphere

22

Geography and the human response to altitude

33

Altitude acclimatization

44

Ventilatory response to hypoxia and carbon dioxide

50

Lung diffusion

65

Cardiovascular system

81

Hematology

97

Blood gas transport and acid-base balance

107

10

Peripheral tissues

119

11

Exercise

130

12

Limiting factors at extreme altitude

142

13

Sleep

156

14

Nutrition and intestinal function

168

15

Endocrine and renal systems at altitude

178

16

Central nervous system

191

vi Contents
17

High altitude populations

202

18

Acute mountain sickness

215

19

High altitude pulmonary edema

232

20

High altitude cerebral edema

247

21

Subacute and chronic mountain sickness

252

22

Other altitude related conditions: neurovascular disorders, eye conditions, altitude cough,
anesthesia at altitude

259

23

Thermal balance and its regulation

271

24

Reaction to thermal extremes: cold and heat

284

25

Hypothermia

294

26

Frostbite and nonfreezing cold injury

306

27

Medical conditions at altitude

322

28

Women, children and elderly people at altitude

329

29

Commercial activities at altitude

336

30

Athletes and altitude

345

31

Clinical lessons from high altitude

350

32

Practicalities of field studies

357

References

365

Index

417

Preface

New advances in the areas of high altitude medicine

and physiology continue to occur at a rapid pace. As
an example of the burgeoning number of publications, a Medline search using the term 'altitude'
retrieves 1566 articles between 1995, when the last
edition of this book was published, and May 2000.
There is ample other evidence of continued growth in
the field. For example, the International Hypoxia
Symposia, which concentrate on high-altitude
medicine and biology, have been held on alternate
years for the past 20 years, with the next meeting
scheduled for March 2001 in Jasper, Alberta, Canada.
In addition, three World Congresses on Mountain
Medicine have interdigitated with the International
Hypoxia Symposia over the last 6 years, with a meeting in Arica, Chile, scheduled for October 2000.
Previous World Congresses were held in La Paz,
Bolivia, Cusco, Peru, and Matsumoto, Japan, emphasizing the breadth of international interest in high
altitude studies. Furthermore there are now at least
three journals exclusively devoted to high altitude life
sciences: one in Japan, another in the People's
Republic of China, and a third recently published in
the United States with a large international editorial
board. In addition, the International Society for
Mountain Medicine publishes a quarterly newsletter.
A feature of high altitude life science studies over
the last 5 years has been the increasing commercial
use of high altitude sites. In the South American
Andes, new mines are being developed at altitudes
above 4500 m, and an interesting facet is that,
increasingly, the miners live at sea level with their
families but commute up to the mine for a period of
perhaps a week, and then return to their families for
the same time. This type of schedule raises many
unanswered questions about the selection and health
of the workers, and their degree of acclimatization.

Additionally, telescopes are being located at very

high altitudes, up to 5000 m. There are now a
number of telescopes at an altitude of about 4200 m
in Mauna Kea, Hawaii, but more recently a 5000 m
high plateau in north Chile at Chajnantor has been
selected for additional telescopic sites. The advantages of the high altitude include the fact that the
instruments are above much of the Earth's atmosphere, and also the Atacama region of north Chile is
characterized by extreme dryness, which also
improves telescope 'seeing.' During the present
decade, the enormous multinational ALMA radiotelescope will be constructed at Chajnantor and, of
course, the logistical problems of working at an
altitude of 5000 m are daunting. A new chapter in
this edition on commercial activities at high altitude
reflects these advances.
All the material in this third edition has been
updated, and there has also been some regrouping
of material to reflect recent advances. New material
has been added in every chapter. Our aim has been
to produce a book that is useful to a wide range of
readers from the ever-increasing number of
climbers and trekkers who would like to know
more about the hazards of high altitude, to
expedition doctors faced with managing high
altitude problems, to researchers who are studying
cutting-edge aspects of high-altitude life sciences.
We have tried to strike a balance between being too
academic on the one hand, and competing with
pocket guides on high altitude emergencies on the
other. As far as we know, no other available text
covers such a wide range of high-altitude life
science topics, including cold injury, with the depth
provided here.
As in the previous editions, we have tried to make
each chapter readable in its own right even if this

viii Preface

means a small amount of repetition of material,

particularly historical points. Few people will read a
book like this from cover to cover. We welcome
constructive criticism, particularly the identification
of factual errors, and will personally respond to every
letter that we receive. We hope that this book will

continue to improve the health and safety of all

people who visit, or live at, high altitude.
Michael P. Ward
James S. Milledge
John B. West

Acknowledgments

We wish to acknowledge help from many friends and

colleagues who have read and commented helpfully
on parts of the text, especially, the late Michael J. Ball
FRCS; F.E. Gallas; the late Eugene Grippenreiter;
Surg. Rear-Adr. Frank Golden OBE, RN; Steven
Hempleman PhD; Michael C. Holdan PhD; Professor
W.R. Keatinge; Sukhamay Lahiri PhD; Robert Mahler
FRCP; the late Betty A. Milledge MB; Odile MathieuCostello PhD; the late Hamish G. Nicol MB; David C.
Poole PhD; Frank L. Powell PhD; Peter D. Wagner
MD; E.J.M. Weaver FRCS; David C. Wellinford PhD;
and Edward S. Williams FRCP.
We gratefully acknowledge the invaluable help of
Amy Clay, Administrative Assistant to JBW, and

Evelyn Denman MB, who read and corrected the

chapters from JSM and MPW. Also we wish to thank
the copy-editor, Kathleen Lyle, and the staff of
Arnold Publishers, especially Joanna Koster and
Wendy Rooke.
We would also like to thank all those who
contributed to the original work on which much of
this book is based. These include Sherpas, climbers,
scientists and other supporters who made the
projects possible.
We especially wish to thank John F. Nunn
FFARCS and Stephen P.L. Travis FRCP who wrote
sections in the previous edition that have been
incorporated into this new edition.

This page intentionally left blank

Conversion tables

Table F.1 Conversion of pressure units mm Hg (millimeters

of mercury) to kPa (kilopascals)

1
10
20
30
40
50
60
80
100
200
300
500
700
760

Table F.3 Conversion of temperature units, C (degrees

Celsius) to F (degrees Fahrenheit)

-40
-30
-25
-20
-15
-10
-5
0
5
10
15
20
25
50
35
40

0.133
1.33
2.67
4.00
5.33
6.67
8.00
10.7
13.3
26.7
40.0
66.7
93.3
101.3

1 torr = 1 mm Hg

-to
-20
-13
-4
5
14
23
32
41
50
59
68
77
86
95
104

Table F.2 Conversion of height units and barometric

pressure according to the ICAO Standard Atmosphere. Note
that in the great mountain ranges the actual pressure will
usually be higher than given by the table (Chapter 2)

Table F.4 Conversion of energy units, kcal (kilocalories) to

kj (kilojoules)

0
1000
2000
3000
4000
5000
6000
7000
8000
9000

0
3281
6562
9843
13123
16404
19685
22966
26247
29258

760
674
596
526
462
405
354
308
267
231

50
100
250
500
1000
2000
3000
4000
5000
6000

209.4
418.8
1047
2 094
4188
8 375
12 563
16750
20 938
25126

This page intentionally left blank

Abbreviations

17-OHCS
2,3-DPG
A-a
ACTH
ADH
AMREE
AMS
ANP
ARPE
AVP
BAL
BCAA
BMR
BTPS
CBF
CCK
CMS
CNS
COLD
CSF
ECF
EGG
EEC
EMG
EPO
ERPF
ET-1
FEV1
FPA
FSH
FVC
GH
HACE
HAGA

17-hydroxycorticosteroid
2,3-diphosphoglycerate
alveolar-arterial
adrenocorticotropic hormone
antidiuretic hormone
American Medical Research Expedition
to Everest
acute mountain sickness
atrial natriuretic peptide
Association pour la Recherche en
Physiologie de 1'Environnement
arginine vasopressin
bronchoalveolar lavage
branched-chain amino acid
basal metabolic rate
body temperature, ambient pressure,
saturated with water vapor
cerebral blood flow
cholecystokinin
chronic mountain sickness
central nervous system
chronic obstructive lung disease
cerebrospinal fluid
extracellular fluid
electrocardiogram
electroencephalogram
electromyelogram
erythropoietin
effective renal plasma flow
endothelin-1
forced expiratory volume in 1 s
fibrinopeptide A
follicle stimulating hormone
forced vital capacity
growth hormone
high altitude cerebral edema
high altitude global amnesia

HAPE
HCVR
HVR
ICAO
iNOS
LH
LVF
MRI
MW
NST
PACo2
Pa

co2

^A02
o2

Pa

Pco2
PCV
PD
PDGF
PI

o2

N2

^02

PRA
PRK
PV
RCM
NREM
REM
RK
RQ
5a

o2
SIDS
SiEp
STPD

high altitude pulmonary edema

hypercapnic ventilatory response
hypoxic ventilatory response
International Civic Aviation Organization
inducible nitric oxide synthase
luteinizing hormone
left ventricular failure
magnetic resonance imaging
maximal voluntary ventilation
nonshivering thermogenesis
alveolar partial pressure of carbon
dioxide
arterial partial pressure of carbon
dioxide
alveolar partial pressure of oxygen
arterial partial pressure of oxygen
partial pressure of carbon dioxide
packed cell volume
potential difference
platelet derived growth factor
partial pressure of inspired oxygen
partial pressure of nitrogen
partial pressure of oxygen
plasma renin activity
photorefractive keratectomy
plasma volume
red cell mass
non-REM (sleep)
rapid eye movement (sleep)
radial keratotomy
respiratory quotient
arterial oxygen saturation
sudden infant death syndrome
serum immunoreactive EPO
concentration
standard temperature and pressure, dry
gas

xiv Abbreviations
SWS
T4
TBG
TGF
TIA

slow wave sleep

thyroxine
thyroxine binding globulin
transforming growth factor
transient ischemic attack

TSH
UKIRT
VEGF

thyroid stimulating hormone

United Kingdom Infrared Telescope
vascular endothelial growth factor

V,02 max

maximum oxygen consumption Kg"1

1
History
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8

Introduction
The Chinese Headache Mountain story
Central and South America: De Acosta
Central Asia: Moguls and Jesuits
Paul Bert
Alpine Club
Balloonists
Late nineteenth and early twentieth century
explorers and physiologists

1
3
3
5
8
8
10
10

1.9
1.10
1.11
1.12
1.13
1.14

Cold injury (hypothermia, frostbite and

nonfreezing cold injury)
The oxygen secretion controversy
The Everest story
Medical and physiological expeditions
Permanent high altitude laboratories
Studies of indigenous high altitude dwellers

12
12
13
15
19
20

SUMMARY

1.1

INTRODUCTION

The effects of cold and high altitude are described by

many early travelers in the highland regions of
Central Asia, South America and elsewhere. Early
balloonists and mountaineers accurately described
acclimatization to altitude, mountain sickness, cold
injury and their after effects.
The measurement of barometric pressure, the
work of Paul Bert and the increasing interest in
mountain regions gave high altitude medicine and
physiology an increasingly scientific basis. Attempts
on, and the first ascent of, Everest provided a catalyst
and scientific expeditions and decompression chamber studies are increasingly common. More and
more studies on high altitude populations are now
being carried out.
The increased understanding of the oxygen transport system at altitude is important for the light it
throws on many clinical conditions at sea level.
To the millions who trek, ski, climb and commute
to altitude each year, together with those who live at
altitude, the subject of high altitude medicine and
physiology is one of increasing importance.

The story of our attempts to climb higher and higher

by our own unaided efforts is one of the most colorful and exciting in medicine and physiology, if only
because scientists have been repeatedly astonished by
mountaineers' ability to ascend higher than their
confident predictions.
About 140 million people live at altitudes above
2500m worldwide (WHO 1996), and each year
some 40 million travel to similar altitudes. This
means that over 180 million people are at risk, and
this number is growing.
Over the centuries investigation into the effects of
human hypoxia and the exploration of the world's
highest mountain ranges have run a parallel and
often overlapping course (Table 1.1).
Numerous clinical and physiological lessons have
been learnt from altitude studies, which share a
number of features found in the chronically hypoxic
patient with cardiovascular and respiratory disorders
(Chapter 31). The physiological problems of altitude
are due in the main to hypoxia and cold: hypoxia
because with gain in altitude there is reduction in

2 History
Table 1.1 Chronology of some principal events in the development of high altitude medicine and physiology

c. 30 BC
1590
1644
1648
1777
1783
1786
1878
1890
1890
1891
1893
1906
1909
1910
1910
1911
1913
1920
1921
1921-2
1924
1925
1935
1946
1948
1949
1952
1953
1960-1
1968-79
1973
1978
1981
1985
1983 to
present
1984 to
present
1990 to
present
1994
1997
1998

Reference to the Great Headache Mountain and Little Headache Mountain in the Tseen Han Shoo (classical
Chinese history)
Publication of the first edition (Spanish) of Natural! and morall historic of the East and West Indies by Joseph
de Acosta with an account of mountain sickness
First description of mercury barometer by Torricelli
Demonstration of fall in barometric pressure at high altitude in an experiment devised by Pascal
Clear description of oxygen and the other respiratory gases by Lavoisier
Montgolfier brothers introduce balloon ascents
First ascent of Mont Blanc by Balmat and Paccard
Publication of La Pression Barometrique by Paul Bert
Viault describes high altitude polycythemia
Joseph Vallot builds high altitude laboratory at 4350 m on Mont Blanc
Christian Bohr publishes Uber die Lungenathmung, giving evidence for both oxygen and carbon dioxide
secretion by the lung
Angelo Mosso completes the high altitude station, Capanna Regina Margherita, on a summit of Monte Rosa
at 4559 m
Publication of Hohenklima und Bergwanderungen by Zuntz et al.
The Duke of Abruzzi reaches 7500 m in the Karakoram without supplementary oxygen
Zuntz organizes an international high altitude expedition to Tenerife; members included C. G. Douglas and
Joseph Barcroft
August Krogh publishes On the Mechanism of Gas-Exchange in the Lungs, disproving the secretion theory of
gas exchange
Anglo-American Pikes Peak expedition (4300 m); participants C. G. Douglas, J. S. Haldane, Y. Henderson and
E. C. Schneider
T. H. Ravenhill publishes Some Experiences of Mountain Sickness in the Andes, describing puna of the
normal, cardiac and nervous types
Barcroft et al. publish the results of the experiment carried out in a glass chamber in which Barcroft lived
in a hypoxic atmosphere for 6 days
A. M. Kellas publishes Sur les possibilites defaire I'ascension du Mt Everest (Congres de I'Alpinisme, Monaco 1920)
International High Altitude Expedition to Cerro de Pasco Peru, led by Joseph Barcroft
E. F. Norton ascends to 8500 m on Mount Everest without supplementary oxygen
Barcroft publishes Lessons from High Altitude
International High Altitude Expedition to Chile, scientific leader D. B. Dill
Operation Everest I carried out by C. S. Houston and R. L. Riley
Carlos Monge M. publishes Acclimatization in the Andes, describing the permanent residents of the
Peruvian Andes
H. Rahn and A. B. Otis publish Man's Respiratory Response During and After Acclimatization to High Altitude
L. G. C. E. Pugh and colleagues carry out experiments on Cho Oyu near Mount Everest in preparation for the
1953 expedition
First ascent of Mount Everest by Hillary and Tensing (with supplementary oxygen)
Himalayan Scientific and Mountaineering Expedition in the Everest region, scientific leader L. G. C. E. Pugh.
Laboratory at 5800 m, measurements up to 7440 m
High altitude studies on Mount Logan (5334 m), scientific director C. S. Houston
Italian Mount Everest Expedition with laboratory at 5350 m, scientific leader P. Cerretelli
First ascent of Everest without supplementary oxygen by Reinhold Messner and Peter Habeler
American Medical Research Expedition to Everest, scientific leader J. B. West
Operation Everest II, scientific leaders C. S. Houston and J. R. Sutton
Research at Capanna Regina Margherita (4559 m) by 0. Oelz, P. Bartsch and co-workers from Zurich,
Bern and Heidelberg
Studies at Observatoire Vallot (4350 m) on Mont Blanc by J.-P. Richalet and co-workers
Research at Pyramid Laboratory, Lohuje, Nepal by P. Cerretelli and co-workers
British Mount Everest Medical Research Expedition, leaders S. Currin, A. Pollard, D. Collier
Operation Everest III (COMEX), leader J.-P. Richalet
Medical Research Expedition to Kangchenjunga, leaders S. Currin, D. Collier, J. Milledge

Central and South America: de Acosta 3

atmospheric and hence oxygen pressure (Chapter 2);

cold because of the temperature lapse with altitude
and wind chill (Chapter 23).
Frostbite is mentioned in a Tibetan medical text
named the Blue Beryl, published in 1688. However, it
seems possible that the text may have originated
much earlier, and a date of 889 BCE has been suggested (Parfionovitch et al. 1992).
Early mountain travelers, like Xenophon, who
crossed the mountains of Armenia following the battle of Cunaxa (401 BCE), were more concerned with
cold than with altitude. Similarly Plutarch
(46-120 CE) tells us that Alexander's army crossing
the Hindu Kush to India in 326 BCE suffered severely
from the 'state of the weather'. One of the earliest
European accounts of the rarefied air of high altitude
was given by the Greeks who, on their yearly ceremonial visit to the summit of Mount Olympus
(2911 m), were not able to survive, we are told,
unless they applied moist sponges to their noses
(possibly soaked in vinegar) (Burnett 1983).
1.2 THE CHINESE HEADACHE
MOUNTAIN STORY
The first documented description of mountain sickness comes from Chinese sources.
In the time of the Emperor Ching-Te (32-7 BCE)
Ke-pin (possibly Afghanistan) again sent an envoy
with offerings and an acknowledgement of guilt. The
supreme board wished to send an envoy with a reply
to escort the Ke-pin envoy home. Tookim (a Chinese
official) addressed the Generalissimo Wang Fung to
the following effect...
From Pe-shan southwards there are four to five
kingdoms not attached to China. The Chinese
Commission will in such circumstances be left to
starve among the hills and valleys ... Again on
passing the Great Headache Mountain, the Little
Headache Mountain, the Red Land, and the Fever
Slope, men's bodies become feverish, they lose
colour and are attacked with headache and vomiting; the asses and cattle being all in like condition.
(Wylie 1881; original Chinese text shown in West
1998 Figure 1.3)

Gilbert (1983a) considers that both the Kilik Pass

and the Mintaka Pass across the Karakoram are possible candidates for the Great Headache Mountain,

but a pass is not a peak, and the Chinese are meticulous observers. Pe-shan, 37.6N 78.2S (Mountains of
Central Asia 1987), mentioned as the starting place,
is situated south-east of Shache (Yarkand) and west
of Hotien (Khotan). From here to Afghanistan there
are a great number of routes across the mountains,
and the one followed has yet to be identified.
Gilbert also draws attention to a case of acute
mountain sickness that was reported by Fa-Hsien
(399-414 CE) who in 403 CE traveled in Kashmir and
Afghanistan. He noted that his companion foamed at
the mouth and later died as they were ascending a
mountain pass. This was possibly a case of high altitude pulmonary edema (HAPE), as the clinical
description is typical.
It has been suggested, too, that the occurrence of
mountain sickness and its complications may have
been taken by the Chinese as a sign for them not to
transgress their natural boundaries (Needham 1954).
13
CENTRAL AND SOUTH AMERICA: DE
ACOSTA
In each inhabited mountain region, whether it is in
Asia, Europe or the Americas (Figure 1.1), there is a
vast depository of legend and folklore. The peaks,
passes and glaciers are deemed to have been created
by a series of gods, Titans and tribal heroes, and individual peaks have been enshrined with virtues and
defects, like any human. For instance, in South
America there is the legend of the trauco found in
southern Chile and Argentina, a mythical animal
that feeds on the blood of animals and human
beings. This is very similar to the yeti legend, found
in the Himalayas and mountains of central Asia
(Napier 1972, Reinhard 1983).
Well-built pre-Columbian structures have been
found near the summit of Llullaillaco (6721 m) and
are probably associated with mountain worship.
Human sacrifice was carried out on these peaks, and
an Inca body has been found at 6300 m on El Toro.
The summits of a number of volcanoes, up to 6425 m
and easily accessible from Arequipa, may have been
used as the altars of sacrificial shrines. These peaks,
with few glaciers and easy rounded slopes, present
little technical difficulty other than altitude and
South American highlanders were used to ascending
to great heights for worship in the late fifteenth century. Altitudes in excess of 6000 m were probably not

4 History

Figure 1.1 South America.

reached on foot in Asia until the later part of the

nineteenth century (Echevarria 1968, 1979, 1983).
In Central America the Spanish Conquistadores
were active in the sixteenth century and in 1519
Cortez sent Diego Ordaz to attempt the ascent of
Mount Popocatepetl (5456 m). Ordaz and companions remarked, 'To increase their distress, respiration
in these aerial regions became so difficult that every
effort was attended with sharp pain in the head and
limbs'. Two years later Francisco Montana and four
Spaniards reached the summit and obtained sulfur
from the crater for the manufacture of gunpowder
(Prescott 1891).
Symptoms of mountain sickness were not

described in any detail by these explorers and it was

left to a Jesuit priest, Joseph de Acosta, to give the
first account. The local names were puna, soroche,
mareo and veta, and the cause thought to be emanations from the metal antimony. In other regions the
vapors from rhubarb, primroses and roses were said
to make men and animals ill. The government of the
Incas clearly understood the effects of climate on
health and it was known, for instance, that people
who lived by the sea died in great numbers if transported to the mines at 3000-4000 m. The cause is
unknown but it is likely to have been a combination
of malnutrition, disease, altitude and cold.
The account of mountain sickness given by Joseph

Central Asia: Moguls and Jesuits 5

H I ST O R IA

N AT V RAL
Y

MORAL DELAS
I N D I A S,
E N CLV E S E T R A T A N LAS C O S A S
notables del ciclo, y elementos, mctalcs, planta.v, y animalcs dellas: y los ritos, y ccrcmonias, Icycs, y
gouierno, y gucrras dc los Indioi.
Compuejrapor elVadrt lofeph desfiofta
dc la Conipania de Irjut.

<%cligiofa

Image Not Available

DIRICIDA ALA SERENISSIMA

Infanta Doiu Ifabclla Clara Eugenia dc Auttria.

CON.
fl^lVlLEClO.
linprcflb en Scuilla c cafa dc luan dc Leon.
Ano dc 159 o.

Figure 1.2 Title page of first edition of Joseph de Acosta 's book
published in Seville in 1590. (Reproduced with permission of the
Bodleian Library.)
de Acosta in The Naturall and Mora// Historie of the
East and West Indies, first published in 1590 in Seville
(Figure 1.2), is worth quoting at length for his
accuracy of description, feelings and cause of the
symptoms:
There is in Peru a high mountaine which they call
Pariacaca ... when I came to mount the degrees, as
they call them, which is the top of this mountaine,
I was suddenly surprized with so mortall and
strange a pang, that I was ready to fall from the top
to the ground and although we were many in company, yet everyone made haste (without any tarrying for his companion) to free himself speedily from
this ill passage ... I was surprised with such pangs
of straining and casting as I thought to cast up my
heart too: for having cast up meate, fleugme and
choller both yellow and greene, in the end I cast up
blood with the straining of my stomach. To conclude, if this had continued I should undoubtedly
have died (de Acosta 1604 p. 146).

However, some reservations have been expressed as

to whether de Acosta was describing acute mountain
sickness (AMS). There is no mention of headache,
and the vomiting in AMS is not usually so severe as
to bring up bile and blood. The possibility that this
was an attack of gastroenteritis should be considered
although diarrhea is not mentioned.
De Acosta's route across the Andes has been investigated by Gilbert (1983b) and, of a number of alternatives, he considers that the pass of the Escaleras de
Pariacaca (4800 m) is the most likely candidate.
Bonavia et al. (1985) have made an on site inspection
of the Pariacaca area and corrected a number of topographical misconceptions. Gilbert (1988) reported
information from mountaineers who had climbed in
the region that, whereas the peak Pariacaca is known
by this name to inhabitants to the south-west (the
direction from which de Acosta made his approach),
it is also known as Tullujuto to those living to the
north-east. The peak is named Tullujuto on the few
maps on which it is marked. It is not unusual for a
peak to have more than one name but this does give
rise to confusion.

1.4 CENTRAL ASIA: MOGULS AND

JESUITS
In 1531, the Moguls invaded Ladakh and western
Tibet (Figure 1.3) and described mountain sickness
which they called 705, and which the Tibetans called
damgiri or dam (breath seizing), or dugri (poison of
the mountain). The clinical features were vomiting,
exhaustion, difficulty in sleeping, aphasia and
swelling of the hands and feet. Death often occurred
unless descent was rapid, and the Mogul sultan, Said
Khan, died of damgiri on the Suget Pass on his way
from Ladakh to Kashgar. This illness was made worse
by cold, and horses also were severely affected. The
Moguls recorded other central Asian names for
mountain sickness: tunk (wakhi and badakhshi), esh
(turki) and bish-ka-hawa (a term used by some
Indian populations of the Himalayas) (Elias and Ross
1898).
In the middle of the seventeenth century there
were rumours of Nestorian Christian colonies living
in central Asia and a number of missionaries from
Rome were sent out to contact them. These remarkable men established missions in Tibet and they were

Figure 1.3 Central Asia.

Central Asia: Moguls and Jesuits 7

among the first Europeans to bring back detailed

information about this mysterious land from first
hand knowledge. Inevitably they suffered from acute
mountain sickness and had views on its cause.
The Jesuit, Father Andrade, was the first European
to enter Tibet. He crossed the Himalayas by the
Mana Pass (5450 m) in 1624 and was more concerned with hypothermia than with hypoxia:
Many people die on account of the noxious vapours
that arise, for it is a fact that people in good health
are suddenly taken ill and die within a quarter of
an hour, but I think it is rather owing to the intense
cold and want of heat, which reduces the heat of
the body (Wessels 1924).

In 1661, two Jesuit fathers, Griiber and D'Orville, left

Peking, and crossed the Tibetan plateau to Lhasa.
Staying a month in the capital they then crossed the
Himalayas by the Thung La, arriving in Kathmandu
several months after leaving Peking. Griiber called
the Himalayas the Langur Mountains and comments
that, 'man cannot breathe in the Langur mountains
because the air is so subtile'. He adds that 'in summer
certain poisonous weeds grow there which extrude
such a bad smell and dangerous odour that one cannot stay up there without losing one's life'. It seems
likely that he was applying Joseph de Acosta's experience to central Asia. Father Desiderei, another Jesuit
who founded a mission in Lhasa in 1716, also comments on the 'reek of certain materials' but goes on
to say that he believes that the unpleasant symptoms
'are due to sharp thin air'. He also suffered from
excruciating headaches.
In 1739 Father Belligatti alludes to the 'singular
influence which mountains exercise over both men
and animals whether this arises from the rarefaction
of the atmosphere or from deleterious exhalations'
(Hedin 1913). This may have been a reference to ladrak as the 'poison of the pass' which was considered
by the Tibetans to be the exhalation of mischievous
gods who caused earthquakes and avalanches
(Landon 1905). Rockhill (1891, p. 149) describes
how mountain sickness was called yen-chang by the
inhabitants of the Koko Nor and chang-chi in
Szechuan. Both expressions mean a 'pestilential
vapour' thought to be given off by the large quantities of rhubarb which grew in the mountains. Eating
garlic and smoking tobacco were held to be antidotes.
In 1845-6 the Abbe Hue crossed the Burhan

Buddha range into north Tibet (Pelliot 1928, Vol. 2,

p. 138). He also complained of'pestilential vapours
and exhalations of carbonic acid' which made him
feel ill and fire lighting difficult. The Russian traveler
Prejavalski (1876) crossed the same pass 30 years
later and correctly attributes his symptoms to 'the
enormous elevation and rarefaction of the air'.
Tutek is another term used by central Asians for
acute mountain sickness (Hedin 1903, Vol. 1, p. 25).
Hedin also describes chronic mountain sickness
occurring in gold miners in north Tibet which may
be fatal (Hedin 1903, Vol. 2, p. 20). The Tibetan remedy for mountain sickness in ponies was to slit their
noses (Bower 1893). In men an incision was made in
the forehead at the hairline (Bonvalot 1891, p. 166).
Other clinical features ascribed to mountain sickness were described by Humboldt (1769-1859), who
in 1802 climbed to 5500 m on Mount Chimborazo in
the Andes of Ecuador (Maggilivary 1853). He and his
companion suffered from bleeding of the lips and
gums as well as malaise and nausea, thought to be
due to low barometric pressure. De Saussure
(Mathews 1898) on the third ascent of Mont Blanc in
1787 also suffered very considerably from fatigue,
thought at the time to be the cause of mountain sickness.
The exploration of the Himalayas began in the
early part of the nineteenth century and symptoms of
mountain sickness were noted by many travelers
including the Schlagintweit brothers, who, in 1855,
climbed to 6785 m on Mount Ibi Gamin in the
Garwhal Himal, a record that stood for 30 years (Von
Schlagintweit and Von Schlagintweit 1862).
The pundits, secret native explorers employed by
the Survey of India, who explored the Himalaya and
Tibet in the nineteenth century (Ward 1998),
describe the total exhaustion of altitude. In 1879 one
pundit had to be carried to the foot of a 6400 m pass
into Tibet, up which steps were cut with a kukri (a
Nepali knife) (Freshfield 1903).
As in Central and South America there are many
myths and much folklore associated with the
Himalaya and mountains of central Asia. One of the
most prevalent is that of the yeti. The yeti story was
given a boost by the discovery in 1951 of the tracks of
bare feet in the snow at about 5000 m in the Menlung
glacier basin west of Everest. These have been attributed to the yeti, but despite much speculation and
many expeditions the yeti has never been found.
Ward (1997), who with Shipton discovered and

8 History

photographed these footprints, suggests that they

could have belonged to a native highlander with an
untreated congenital or acquired abnormality of the
foot, who was able, like many other high altitude
people, to walk barefoot in the snow for many hours
because of marked cold tolerance (see section
24.1.3). Schaller (1998) makes no mention of theyeti
myth in his comprehensive work on wildlife of Tibet.

1,5

PAUL BERT

During the nineteenth century in Europe considerable interest in experimental physiology was being
generated by Claude Bernard. Paul Bert, a pupil of
his, was born in 1833 and the study of the medical
aspects of low barometric pressure and resulting
hypoxia was one of his many interests; he is recognized as the father of altitude physiology. He was the
first to conduct experiments in a decompression
chamber where he studied the effects of both reduced
and increased barometric pressure in small animals
and humans. He showed that breathing air under
conditions of reduced barometric pressure as at altitude was dangerous because of oxygen lack, whereas
breathing oxygen even under reduced pressure
restored function.
Bert collected accounts from travelers and scientists from all over the world and, in addition to his
work in steel decompression chambers, which were
donated by his patron Dr Jourdanet, he became
interested in the opportunities that balloon flights
offered for the study of altitude physiology.
The first 350 or so pages of his classic work La
Pression Barometrique are considered to be the most
authoritative early account of the history of the physiological effects of decreased atmospheric pressure
(Bert 1878) (Figure 1.4). His work did not go uncriticized, particularly by Mosso and Kronecker (Kellogg
1978). Kellogg also points out that Kronecker
reviewed various case histories including one diagnosed as pulmonary edema at autopsy. Mosso
(1898), who was Professor of Physiology at Turin,
made good use of the Capanna Regina Margherita on
the Punta Gniffeti (4560 m), one of the summits of
Monte Rosa, constructed by the Club Alpino Italiano
(Figure 1.5). He did not believe that mountain sickness was due to lack of oxygen but thought it was due
to lack of carbon dioxide. He was a major figure in

Figure 1.4 Title page of Paul Bert's book La Pression

Barometrique, published in Paris in 1878.

altitude physiology, tracing the breathing pattern of

periodic respiration; he also published the first clinical report of pulmonary edema.

1.6

ALPINE CLUB

In the middle of the nineteenth century mountain

travel was becoming increasingly popular and the
Alpine Club was founded in the UK in 1857. The
Alpine Journal, 'a record of mountain adventure and
scientific observation' contained a number of articles
on mountain sickness in its early issues. Count
Henry Russel (Russel 1871) comments that mountain sickness was 'known all over the world (though
less in the tropics)... and in the Himalaya where the
silly natives attribute it to the exhalations of a venomous plant'. Spinal anemia, the result of diminished atmospheric pressure, was suggested as a cause
of the weakness of the lower limb 'which was so

Alpine Club 9

Figure 1.5 European Alps.

prominent a feature of mountain sickness' (Monro

1893).
A year later Thomas (1894) thought that the very
dry air of Tibet and the Karakoram might be a factor,
as the overall effect of altitude was felt there at a
lower level than in damper Sikkim. A review of the
eighteenth and nineteenth century theories on
mountain sickness and its cause is given by Hepburn
(1901, 1902). He suggests that following certain
training, dietary and breathing routines, a man could
climb to 30 000 ft (9144 m). He concludes: 'but even
so we have yet to prove that dyspnoea and fatigue are
dependent on lack of oxygen at any level either
directly or indirectly, though the probabilities are in
favour of such a theory'.
In a salutary article on alcohol and climbing,
Marcet (1886-8b) writes that mountain sickness 'is
certainly neither protected against nor relieved by
the use of alcoholic beverages'. He ends by saying
that, 'strong drinks do not give strength, and as a
means of keeping the body warm they go in the

opposite tack doing away with the natural powers

that man possesses of resisting cold, thus acting as a
delusion and snare'. Albutt (1876) in fact considered
that the use of alcohol predisposed to frostbite.
Earlier, Albutt (1870) had observed that the hard
exercise of climbing accelerated the 'morning rise in
temperature' (taken sublingually). However, rectal
temperatures in two guides taken during the ascent
of Monte Rosa showed a rise in one and a fall in the
other (Payot 1881). Payot also considered that the
increased respiration of climbing was associated with
an increase in water loss from the lungs and poor
urine output, a fact confirmed by Pugh in 1952.
Marcet (1886-8a) suggested that potassium chlorate be taken, as when it is heated it gives off oxygen
and would combat the effects of altitude. He observed
that it had been used by Sir Douglas Forsyth in the
'Cashmere mountains on the way to Kashgar' and by
Whymper on the first ascent of Chimborazo. It is
clear from Bellew (1875) that the salt was eaten!
In 1879 Edward Whymper, the conqueror of the

10 History

Matterhorn, mounted an expedition to the Andes of

South America specifically to study mountain sickness. He divided the clinical effects into permanent
(which included poor appetite, fatigue and increased
respiration) and transient (increase in blood pressure, temperature and heart rate) (Whymper 1892,
pp. 366-84).

1.7

BALLOONISTS

Whilst observations on mountain sickness were

being made by mountain travelers, more dramatic
episodes were occurring to balloonists.
The Montgolfier brothers, Etienne and Joseph, the
most famous pioneers of early ballooning, made the
first ascent in a hot air balloon in November 1783,
and, in the same month, De Rozier, a French apothecary, and the Marquis d'Arlandes, crossed Paris in a
'Montgolfier'. In the same year the physicist Charles,
who had invented the hydrogen balloon, left the
Tuileries and landed 2 h 45 min later in the plain of
Nesles. Roberts, his companion, disembarked here
and the lightened balloon rose to over 1500 fathoms
(approximately 2740 m). Later Gay-Lussac ascended
to over 7000 m, noticing that both his pulse and respiration were much increased.
Nearly a century later in September 1862, Coxwell
and Glaisher, two English meteorologists were carried to 8800 m, escaping death only because Coxwell
managed to pull the release valve with his teeth.
Glaisher (Glaisher etal 1871) made a number of further flights and considered that he had developed a
tolerance to altitude. Though a decrease in barometric, and therefore oxygen, pressure had been demonstrated on these ascents, the early balloonists had still
not fully grasped that the dangers at altitude were
due to hypoxia.
In March 1874 Croce-Spinelli and Sivel came to
Paul Bert's laboratory before an attempt on the balloon altitude record. Following decompression
chamber experiments the balloonists were convinced
of the effectiveness of oxygen but planned to carry
too little for safety. Bert was alarmed and wrote indicating it was not enough but the letter arrived too
late. On 15 April 1875, the balloon named Zenith
rose to around 8000 m; Tissandier, the survivor,
described in detail the features of hypoxia which
killed his two companions and would have killed him

if he had not vented some hydrogen which caused

Zenith to descend (Tissandier 1875) (Chapter 16).

1.8 LATE NINETEENTH AND EARLY

TWENTIETH CENTURY EXPLORERS AND
PHYSIOLOGISTS
In the late nineteenth and early twentieth centuries
there was increasing medical and scientific interest in
both the oxygen transport system and altitude adaptation, and many discoveries were made. Viault
(1890) recorded the best known physiological
response to altitude, namely an increase in the number of red cells. He found a rise from 5.0 million at
sea level to 7.5-8.0 million at Morococha (4550 m)
and observed that this change took place over a short
period. By contrast, Bert had thought that it took
place gradually over generations at altitude (Chapter
7). Later, Hingston (1914) considered that the symptoms of mountain sickness were due to failure to
increase the number of red cells on ascent to high
altitude.
Disorders of respiration that had the 'Stokes character' were also described at 4400 m (Egli-Sinclair
1891-2, 1894). A similar episode had been noted by
Hirst in 1857 when he made an ascent of Mont Blanc
with the well known physicist and mountaineer
Professor J. Tyndall. Tyndall fell asleep on the summit and Hirst roused him saying 'I have listened for
some minutes and have not heard you breathe once'
(Tyndall 1860). Periodic respiration had, in fact,
been described by the surgeon John Hunter in his
case records in 1781 (Ward 1973) over 30 years
before Cheyne's paper (Cheyne 1818) (Chapter 13).
Though a case of pulmonary edema due to altitude
had been recorded by Kronecker at autopsy (Kellogg
1978), it is likely that the first full clinical description
occurs in Mosso's book Life of Man on the High Alps
(Mosso 1898, pp. 289-92). The victim, Dr Jacottet,
died on Mont Blanc at 4300 m, and the autopsy
report attributed the waterlogged lungs to pneumonia. Later, Ravenhill (1913), the medical officer of a
mine in South America, differentiated between a
cerebral and a cardiac form of mountain sickness, the
latter being now regarded as pulmonary edema.
Twenty years later Hurtado (1937) suggested that the
pneumonia or pulmonary edema of altitude was not
due to infection but altitude per se and Lundberg pre-

Late nineteenth and early twentieth century explorers and physiologists 11

sented six cases of acute pulmonary edema to the

Asociacion Medica de Yauli. Lizarraga (1955) published (in Spanish) the first series of cases of HAPE
since Ravenhill, collected in Peru in 1951-2.
A case that was clearly HAPE, and in which the
patient died, was reported in a letter to Pugh, commented on by him and published in the UK (Pugh
1955a). Pugh's comment indicated that the condition was unknown to him at the time.
In 1959 Hultgren visited Chulec General Hospital
in Oroya, Peru, and found HAPE was a well known
condition (Hultgren and Spickard 1960). Houston
(1960) 'rediscovered' the condition, since when it has
become widely recognized (Chapter 19).
Commercial groups were starting to build railways
into the mountains to improve access and boost
tourism, and plans were discussed for a railway to the
top of the Jungfrau, in Switzerland. The scientific
investigations were carried out on the Theodule Pass
(3500 m) between Zermatt and Cervinia in 1894
(Kronecker 1903). Eventually this railway was built
as far as the Jungfraujoch. The dangers to elderly
travelers and those with angina pectoris of ascent by
railway to even moderate altitude were discussed by
Zangger(1899, 1903).

Though minor vascular disorders were often

reported at altitude, the first major vascular accident
to be reported occurred to a Russian traveler,
Roborovsky (1896), while crossing the Mangur Pass
(4270 m) in east Tibet. He suffered a transient stroke
and it was 8 days before he could move (Chapter 22).
The tempo of Himalayan exploration accelerated
in this period and Conway on Pioneer Peak (7000 m)
in 1892 described the debilitating effects of long periods at high altitude. He also took sphygmograph
pulse records at intervals up to and including the
summit (Figure 1.6). His resting pulse remained
between 90 and 100/min, but there is one reading at
6100 m when it was 48. Could this have been an incident of transient 2:1 heart block (Roy 1894)?
By contrast, the Duke of Abruzzi's expedition to
the Karakoram in 1909 climbed to 7500 m with few
of the symptoms due to altitude. Interestingly, however, Filippi (1912, p. 364) also reports 'the atmosphere of the expedition did work some evil effect
revealing itself only gradually after several weeks of
life above 17 500 ft', and he goes on to give a description of high altitude deterioration (section 4.2.2).
Anticipating the modern trend, some amazingly
fast ascents were made, particularly by Longstaff, a

Image Not Available

Figure 1.6 Pulse sphygmograph

records on Pioneer Peak (7000 m)
taken by Conway in 1892 (from Roy
1894). Note resting pulse of 48 beats
per minute in Figure 8, possibly due to
2:1 heart block. (Reproduced with
permission of the Library of the Royal
Geographical Society.)

12 History

British physician, who ascended 2000 m to 7180 m in

10 h on Mount Trisul (section 1.11). He was also one
of the first to recognize that sugar was of great
importance in the diet at high altitude (Longstaff
1906, 1908).
Waddell, Medical Officer on the British
Expedition to Lhasa 1903-4, supplies an amusing
vignette:
A peculiarity of the language of the Tibetans in
common with the Russians and most arctic nations
is the remarkably few vowels in their words and the
extraordinarily large number of consonants. Indeed
so full of consonants are Tibetan words that most of
them could be articulated with an almost semiclosed mouth, evidently from the enforced necessity to keep the lips closed as far as possible against
the cutting cold when speaking (Waddell 1905).

German contributions before and during World

War I were considerable. Before the war Nathan
Zuntz had worked on the relationship between barometric pressure and altitude in the European Alps
(Zuntz et al. 1906) as well as on other aspects of altitude physiology with many well known physiologists
of his time, including Durig, Douglas, Barcroft,
Loewy and Pfluger. After the war, with the rise of
National Socialism, aviation and high altitude medicine burgeoned, as did mountaineering. In 1931 a
German expedition to Kangchenjunga had Hans
Hartman as its physiologist and in the two German
parties to Nanga Parbat in 1937 and 1938, Ulrich
Luft took part. He later became an American citizen.
Both Hartmann and Luft were interested in erythropoiesis at altitude. Luft also showed that altitude
acclimatization could be preserved by daily exposure
to 5000 m in a decompression chamber (Bauer 1938,
Hartmann et al. 1942).
World War II played an important role in the history of high altitude medicine and physiology
because it provided much increased activity in environmental and respiratory physiology. Individuals
from different branches of medicine and physiology
were brought together with a strong sense of common purpose and one remarkable combination was
that of Wallace Fenn (plant physiologist), Herman
Rhan (zoologist) and Arthur Otis (physiology of
pressure breathing), who worked at the University of
Rochester, New York. They carried out many studies
for the US Air Force which culminated in the construction of the Rhan-Otis oxygen/carbon dioxide

diagram which relates the composition of alveolar

gas pressures in acclimatized and unacclimatized
humans exposed to altitude (Rhan and Otis 1949).
Also the foundation of the Journal of Applied
Physiology can be traced to them.

1.9 COLD INJURY (HYPOTHERMIA,

FROSTBITE AND NONFREEZING COLD
INJURY)
For many centuries cold injury has been known to
travelers in polar and highland regions and armies in
the field, but it is relatively recently that specific disease patterns have been described. Local cold tolerance but not general acclimatization to cold is
recognized amongst Inuit peoples, polar travelers,
mountaineers and central Asian highlanders.
Hypothermia or general cold injury may affect
climbers at extreme altitude even when fully clothed.
It also occurs at sea level at temperatures above freezing when wetting and wind degrade the insulation of
clothing. Nonfreezing cold injury (immersion
injury) was common in the armed forces pinned
down by trench warfare in World War I and in
lifeboat survivors in World War II. Frostbite is
described in early Tibetan medical texts dating back
many centuries but its management by rapid
rewarming is a relatively recent therapy (Mills and
Whaley 1960, Marsigny 2000).
The term 'wind chill' was coined by Siple in 1945
to express the concept that on a windy day one feels
much colder than on a calm day at the same temperature (Siple and Passell 1945, Paton 1999). The concept of wind chill was re-examined by Danielsson
(1996), who considered that Siple and Passel had
underestimated the effect of air speed.

1.10
THE OXYGEN SECRETION
CONTROVERSY
The ascent to 7500 m by the Duke of Abruzzi's party
amazed many physiologists, for it was thought that
lung diffusion was inadequate for extreme exercise at
low oxygen pressure. However, it was becoming
apparent that in some organs 'chemicals' could move
against the concentration gradient. If the lungs could
secrete oxygen this might explain both the variability

The Everest story 13

with which individuals reacted to altitude and also

their ability to ascend so high.
The arguments deployed for and against this
theory are reviewed in Chapter 6. Initially, in favor of
secretion was the theoretical impossibility of the diffusion of 5-6 L of oxygen across the lung each
minute during extreme exercise. However, at the
turn of the century, Marie Krogh measured the diffusing capacity of the lung to carbon monoxide,
from which the diffusing capacity of oxygen could be
inferred. She showed that the lung was a very good
diffuser of oxygen partly because of its enormous
surface area and partly because of the affinity of
hemoglobin for oxygen. However, her work was
ignored, being rediscovered in the 1930s.
Haldane and Barcroft were both distinguished respiratory physiologists though they held opposing
views. After a number of investigations, including
the Cambridge 'glass box' experiment of Barcroft,
and expeditions to high altitude by groups led by
both workers, Barcroft finally showed conclusively
that the arterial Po2 was always lower than the alveolar Po2. The diffusion theory was correct and
Barcroft's book, Lessons from High Altitudes, became
a classic work on the subject (Barcroft 1925, Milledge
1985).

1.11

THE EVEREST STORY

In 1921, after years of prevarication, the government

of Tibet gave permission for a British party to
attempt Mount Everest from the northern Tibetan
side.
The individual who knew most about the physical
and physiological problems that would be encountered was Alexander Kellas, a lecturer in chemistry at
the Middlesex Hospital Medical School. He had
made a number of expeditions to the Sikkim Himal
and the Tibetan border before World War I and had
become increasingly interested in the problems of
altitude (Kellas 1917).
Before he went on the first Everest reconnaissance
expedition in 1921, Kellas wrote a paper entitled 'A
consideration of the possibility of ascending Mount
Everest'. Unfortunately he died on the approach
march at Kampa Dzong on the Tibetan plateau,
within sight of the mountain, and this paper was
never published, though copies of the manuscript

were lodged in the archives of the Royal

Geographical Society and the Alpine Club (West
1987). In it he considers both the difficulties of access
and the physiological problems. The section of the
1921 manuscript entitled 'The process of acclimatisation to altitude' is of great interest because
although there are many factual errors his insight in
asking the correct questions was uncanny.
As Kellas saw it, the main issue was whether sufficient adaptation could occur to allow a climber to
ascend from a camp at about 7700 m to the summit
(8848 m) in one day without supplementary oxygen.
His conclusion was that this was possible and, in fact,
the first such ascent by Habler and Messner in 1978
started from a camp at 7950 m. He calculated too
that the barometric pressure on the summit would be
251 mm Hg, a more accurate figure than estimates
based on the 'standard atmosphere' (Chapter 2). The
current value of 253 mm Hg was measured on the
summit by the American Medical Research
Expedition in 1981. Kellas estimated the maximum
oxygen uptake on the summit to be 970 mL min '
and the current value is thought to be about
1070 mL min-1. As far as climbing rate near the summit, his estimate of 100-120 m h-1 closely parallels
the rate of Habler and Messner: 'The last 100 m took
us more than one hour to climb.' Finally, he thought
that humans could live indefinitely at 6100 m.
Some of the few values for which Kellas's figures
were too low were alveolar Po2, oxygen saturation
and arterial pH; this was because he underestimated
the degree of hyperventilation and assumed a normal
arterial pH.
It is difficult to assess the probable effects of this
paper had it been published, but at least it might have
encouraged subsequent expeditions to consider
more fully the scientific aspects of the ascent.
The series of expeditions between 1921 and 1953,
the year of the first ascent, give a fascinating insight
into the effects of altitude and cold and the attitude
of mountaineers towards climbing the highest
mountain in the world. It soon became obvious that
the main obstacles to the ascent were altitude and
weather, and not technical difficulty. The main controversy was whether supplementary oxygen should
be used and this was compounded by personality
clashes. The medical preparations for the first Everest
expeditions in 1921, 1922, and 1924 were very
thorough.
In 1920, Kellas and Morshead of the Survey of

14 History

India went to Kamet, a peak of over 7000 m in the

western Himalayas, on behalf of the Everest
Committee of the Alpine Club and Royal
Geographical Society, to test primus stoves and oxygen equipment. At the suggestion of Professor
Leonard Hill of Oxford, Oxylite bags containing
sodium peroxide which when mixed with water gave
off oxygen were also taken (Kellas 1921, Morshead
1921).
Because neither the primus stoves nor the oxygen
cylinders worked satisfactorily, the stoves were tested
in the decompression chamber at the laboratory of
Professor Dryer at Oxford University in 1921. Dryer
had strong views on the use of supplementary oxygen
on Everest: 'I do not think that you will get up without, but if you do you might not get down again.' In
March 1921, before the first reconnaissance of
Everest left for India, Finch, a possible member of the
party and later professor of physical chemistry at
Imperial College London, and two members of the
committee witnessed the stoves being tested in the
decompression chamber. Dryer easily convinced
Finch that supplementary oxygen should be used on
Everest, and persuaded him to stay overnight. Next
day he was decompressed to 6400 m and exercised
both with and without supplementary oxygen. Not
surprisingly, without the benefit of acclimatization,
Finch was convinced of the benefit of supplementary
oxygen at altitude.
As the 1921 expedition was for reconnaissance
only, supplementary oxygen was not taken. In preparation for the 1922 attempt on the summit, Finch
returned to Oxford in January 1922 with another
party member, Somervell, a surgeon, and took part
in further experiments, being decompressed to
7010 m. It was because of these experiments that
supplementary oxygen was used in 1922. In 1922
four men ascended to 8250 m without supplementary oxygen and two men reached a similar height
using it. Many clinical features of chronic hypoxia
were recognized: poor appetite, loss of weight, dehydration, exhaustion and failure to recover from
fatigue being the most obvious (Unna 1922).
Finch, confirming the observations of Paul Bert,
noted the beneficial effects of using oxygen.
However, in 1924 Odell spent 11 days above 7000 m,
climbing on two occasions to 8300 m without supplementary oxygen (Bruce 1923, p. 237, Norton
1925, pp. 120-43). His performances were equal to
those using supplementary oxygen; but when he used

supplementary oxygen at 1 L min-1 there was no

improvement, and this observation clouded the clinical picture. Also, as Sherpa porters carrying loads
without supplementary oxygen ascended as fast as
those with it, an element of uncertainty was introduced which was not resolved until the work of Pugh
in 1952 on the Menlung La (5800 m) in the Everest
region (see below). Another feature of high altitude
was emphasized by Mathews who considered that
loss of heat could occur through increased respiration (Mathews 1932). However, it is now apparent
that the upper respiratory tract acts as a very efficient
heat exchanger.
Successive expeditions in 1933, 1935, 1936 and
1938 failed to ascend higher than 8500 m, mainly
because supplementary oxygen at 2 L min ' only was
used and this failed to increase climbing rate. After
World War II the Nepalese side of Everest was visited
in 1950 by an Anglo-American party that included
Houston and Tilman, and in 1951 a British party led
by Shipton revealed a possible route. In 1951 too,
investigations into the scientific problems posed by
Everest were started in London by Pugh of the
Medical Research Council under the general guidance of Professor Sir Bryan Mathews. The following
year, 1952, a Sherpa, Tensing, and Lambert, on a
Swiss attempt, reached 8500 m using oxygen intermittently, but not only was their flow rate of oxygen
inadequate to compensate for the weight of the sets,
they were also grossly dehydrated (Dittert etal. 1954).
In the same year a British mountaineering and scientific party visited a neighboring peak, Cho Oyu
(8153 m), and Pugh carried out scientific work in a
tented laboratory at 5800 m on the Menlung La
which was vital to the subsequent ascent of Everest in
1953.
The most important outcome was the development of a reliable and not too heavy open-circuit
oxygen apparatus which delivered oxygen at various
flow rates between 2 and 6 L min-1, much higher than
the flow rates used on all previous expeditions. This
compensated for the weight of the set and increased
climbing rate sufficiently so that the mountaineer
could ascend to the summit from a high camp and
descend safely within the hours of daylight. The use
of supplementary oxygen of 4 L min-1 above 7500 m
was the single most important reason for the first
ascent of Everest in 1953. It transformed climbers at
extreme altitude from 'sick men walking in a dream'
to individuals capable of overcoming reasonable

Medical and physiological expeditions 15

difficulties, making good decisions and climbing

through bad weather. Other causes for previous failures were the marked dehydration at extreme altitude (due partly to respiratory water loss through
increased respiration and partly to inadequate fluid
intake due to difficulty in melting enough snow); levels of food intake; and clothing insulation (Pugh
1952, 1954, Milledge 1992, Ward 1993a). The work
of Pugh in 1951 and 1952 was one of the primary reasons for the success of the 1953 expedition.
The consecutive expeditions in 1951, 1952 and
1953 also enabled the basic clinical features of altitude exposure up to 8848 m to be established (Pugh
and Ward 1956). On the first successful ascent of
Everest, Hillary and Tensing removed their oxygen
masks on the summit. Hillary (1954) remarks: 'I had
now had my oxygen mask off for nearly eight minutes and was becoming rather clumsy fingered ...
We put on our oxygen masks and set off from the top
down the way we had come.'
In 1978, Everest was climbed for the first time
without using supplementary oxygen by Habeler and
Messner (Messner 1979, pp. 174-80). They had little
in reserve: 'After every few steps we huddled over our
ice axes mouths agape struggling for sufficient
breath', and the last 100 m took more than 1 h. Over
50 such ascents have now been made without supplementary oxygen both by sea level visitors and by high
altitude residents, though the mortality rate amongst
those attempting such an ascent is high.
In October 1981 the barometric pressure on the
summit of Everest (8848 m) was measured for the
first time by Pizzo. It was found to be 253 mm Hg
and in May 1997 a further direct measurement on
the summit was found to be within 1 mm Hg of this
figure. Measurements on the South Col (7986m) in
the summer of 1998 showed mean values in May of
284 mm Hg; June 285 mm Hg; July 286 mm Hg; and
August 287 mm Hg. It appears therefore that on the
days when Everest is usually climbed, that is between
May and October, the barometric pressure on the
summit is between 251 and 253 mm Hg (West
1999a).
A Sherpa, Ang Rita, has reached the summit on ten
occasions and made the first winter ascent in
December 1987, without supplementary oxygen
(Mountain 1988).
By the end of 1992, 425 individuals had climbed
Everest (Gillman 1993). By 1999 over 1000 people
had made this ascent using supplementary oxygen,

including 54 women who had a mortality of 7.4%.

The mortality rate in men was 3.2%. One hundred
ascents have been made without supplementary oxygen, but with a mortality rate of 6%. By the end of
1999 the total number of deaths on Everest was 171
(Unsworth, 2000).
Following the example of Longstaff, some very
rapid ascents and descents of Everest have been
made. In 1986 two mountaineers climbed the North
Face by the Hornbein Couloir without supplementary oxygen. They started from the West Rongbuk
glacier (5800 m) at 22.00 h and in 12 h, overnight,
reached a bivouac at 7800 m. Here they rested, then
they ascended to the summit (8848 m), arriving at
14.30 h. After spending 1 h 30 min on the top they
descended to their bivouac in 3 h. From there to the
glacier (5800 m) took only 2 h (Everest 1987). The
fastest Everest ascent took 22.5 h from Base Camp to
summit (Gillman 1993).
In 1856 the height of Everest was estimated to be
29002ft, 8940m (the average of six readings).
Following the opening of Nepal in 1950, B.L. Gulatee
of the Geodetic and Research branch of the Survey of
India observed Everest from between 29 and 47 miles
and computed a height of 29 028 (0.8 ft), 8848 m. In
1999 a height of 29035 ft (8850 m) was calculated
using global positioning satellite equipment (Gulatee
1954, Ward 1995, The Times 1999a).

1.12
MEDICAL AND PHYSIOLOGICAL
EXPEDITIONS
Although medical and physiological observations
have been made on expeditions from the earliest
times, probably the first series of investigations
mounted primarily to study the physiology of high
altitude was that of Angelo Mosso at the end of
the nineteenth century. In the early years of the
twentieth century Barcroft and Haldane, with their
co-workers, were also involved in a series of research
programs in Tenerife, the European Alps, Pikes Peak
and Cerro de Pasco.
In 1935 the International High Altitude
Expedition went to the Andes. They spent several
months in Chile studying many aspects of acclimatization to altitude including lactacidosis on exercise,
the acid-base status of the blood and arterial blood

16 History

gases, both in members of the expedition and in local

residents at various altitudes (Dill 1938).
In 1946 'Operation Everest' was carried out at
Pensacola Naval Air Station in Florida. Four volunteers lived in a decompression chamber for 34 days,
reaching 6600 m on day 27 after gradual decompression. On day 30 the chamber was decompressed to
235 mm Hg - equivalent to 8850 m on the standard
atmosphere scale (Chapter 2).
Two men were able to tolerate this altitude for
30 min 'on the top of Everest'. The results strongly
suggested a diffusion limitation of oxygen transfer
during exercise (Houston and Riley 1947). A similar
investigation, 'Operation Everest II', was completed

in 1985 at the US Army Institute of Environmental

Medicine at Natick, Massachusetts (Houston et al
1987). The ascent profiles of Operation Everest and
Operation Everest II were similar except that in the
latter the ascent was more rapid and subjects spent
longer at extreme altitude. Cardiac catheterization
was possible at extreme altitude and important new
information was obtained on pulmonary gas
exchange. Muscle biopsies were also completed as
well as psychometric tests and sleep studies.
Although Pugh made important physiological
observations on Cho Oyu in 1952 and on Everest in
1953, the next expedition devoted to high altitude
physiology was in 1960-1, which was led by Hillary

Figure 1.7 The Silver Hut with Rakpa Peak in

the background (taken at 5800 m during the
Himalayan Scientific and Mountaineering
Expedition in the Everest region, 1960-1).

Figure 1.8 Bicycle ergometer being assembled

at 7400 m on the Makalu Col by Ward and
West, 1961.

Medical and physiological expeditions 17

with Pugh as scientific leader. A fully equipped physiological laboratory, the Silver Hut, was installed at
5800 m in the Everest region. The results from this
expedition have formed the basis for much subsequent investigation into extreme altitude, and the
expedition was an important landmark in high altitude studies. The Silver Hut was occupied for
6 months between November 1960 and May 1961
(Figure 1.7), and an attempt on Mount Makalu
(8481 m) was also made when maximum work studies were completed at 7440 m by West and Ward
(Figure 1.8). This still remains the highest altitude at
which such studies have been made.
Projects included studies on exercise, lung diffusion, changes in the control of breathing, electrocardiograph (EGG) changes, basal metabolic rate,
blood volume and hemoglobin changes, and psychomotor function. Two vascular accidents occurred
- one cerebral, the other pulmonary; there was ample
evidence to suggest that, despite good living conditions, all participants deteriorated during long-term
residence at 5800 m (Pugh 1962a).
The next 20 years saw a number of field investigations into the physiology and medicine of high altitude and an increasing number of people - skiers,
trekkers and tourists, as well as mountaineers - were
going to high altitude all over the world.
In 1962 the Indian Defence Authorities arranged a
'symposium on the problems of high altitude' at
Darjeeling (Symposium (Indian) 1962). This was
during the period when China was threatening the
northern Himalayan border of India. The Indians
appreciated that the Chinese, who had acclimatized
for long periods on the Tibetan plateau, would be at
an advantage in any conflict in the Himalayas, as
Indian soldiers, who lived at low altitude, would not
have had time to acclimatize.
In 1964 China did invade India; the Indian soldiers
suffered considerably from acute mountain sickness
and HAPE. The work of Inder Singh and his colleagues
dates from this period (Singh etal. 1969b). Since then
the clash between India and Pakistan on the Siachen
glacier of the Karakoram has provided an added stimulus to high altitude studies in both countries.
In 1967 a permanent laboratory was placed at
5300 m on Mount Logan in Alaska (Figure 1.9) and
this was visited regularly by medical scientists until
1979. During these years, studies included retinal
blood flow, the incidence of retinal hemorrhage and
the value of acetazolamide in preventing acute

mountain sickness. Evidence of subclinical pulmonary edema on ascending to the laboratory was
found in many subjects (Houston 1980).
Studies on acute mountain sickness and the use of
acetazolamide have also been carried out by groups
from Birmingham, UK (Acute mountain sickness
1979, 1987).
On the successful Italian expedition to Everest in
1973, Cerretelli made an extensive series of measurements at 5350 m on climbers who had been to
8000 m. One of the many interesting observations
was the failure of maximum oxygen uptake of subjects acclimatized to 5350 m to return to sea level values when pure oxygen was breathed. Noted also by
Pugh and others, this finding has never been satisfactorily explained (Cerretelli 1976a).
In 1980-1 a Sino-British team explored the
Kongur Massif in Southern Xinjiang, Chinese central
Asia, climbing Kongur (7719 m), the highest peak in
the Kun Lun range which runs along the northern
edge of the Tibetan plateau (Ward 1983). Half the
team were medical scientists and work was done on
the cardiorespiratory response in elite mountaineers,
on erythropoietin changes with ascent to altitude
(Milledge and Cotes 1985), and on the reninaldosterone system (Milledge 1984).
In 1981 West led the American Medical Research
Expedition to Everest (AMREE). The barometric
pressure, measured for the first time on the summit,
was found to be 253 mm Hg. This was higher than
predicted by some authorities (Chapter 2). Alveolar
gas samples were taken on the summit of Everest for
the first time by Pizzo and very low Pco2 values were
observed, indicating extremely high ventilation rates
at rest. Pizzo and Hackett also obtained blood samples on the South Col from which it was deduced that
there would have been extreme alkalosis on the summit (Chapter 12). In the Western Cwm a fully
equipped laboratory was set up and important observations made on exercise, sleep, metabolism, nutrition, hormones and psychomotor function (West
1982a, 1985a). AMREE 1981, which developed from
the Silver Hut Expedition (1960-1), and Operation
Everest II (1985), which followed from Operation
Everest I (1946), were both extremely successful and
complemented each other.
Operation Everest II had the advantage that complex and invasive techniques could be carried out
and any subjects who became ill could be removed
from the chamber. Its disadvantage was the artificial

18 History

Figure 1.9 North America.

environment and shorter time available for acclimatization. AMREE 1981, of course, had to contend
with the climatic factors of Everest. The cost of each
investigation was similar, and taken together these
four studies have made an enormous contribution to
understanding the physiological and medical challenges of high altitude.
In the last 25 years too, numerous expeditions
have been made on the Tibetan plateau by the
Academia Sinica, including a traverse of the plateau
by a Royal Society-Academica Sinica party in 1985

(Dong-Sheng 1981, Chang etal. 1986). In the course

of these expeditions a number of peaks, including
Everest, have been climbed and high altitude work
carried out by members of the Shanghai Institute of
Physiology led by Professor Hu Hsu-Tsu and other
groups. During the Chinese ascent of Everest in 1975
telemetry of the heart was carried out and a number
of other studies made (Shi etal. 1980, Hu 1983).
Russian contributions have been considerable. The
most important early work on the effects of rarefied
air on humans came from I.M. Sechenov after the

Permanent high altitude laboratories 19

deaths in the balloon Zenith in 1875. He studied the

oxygen transport system, which formed the basis of
later work on high altitude and in aviation.
At the end of the nineteenth century, P.
Gorbachev, N. Tretiakov and O. Shlomm studied the
effects of adaptation to altitude on soldiers in the
Pamir and Tien Shan, probably in association with
the 'great game' or rivalry with Britain for political
influence in Central Asia.
The year 1923 saw the birth of Soviet mountaineering with the ascent of Mount Elbruz in the
Caucasus. The first scientific expedition took place in
1926 and, between then and the outbreak of war with
Germany in 1941, 25 expeditions from three main
centers, Leningrad Military Medical Academy,
Moscow and Kiev, took place in the Caucasus,
Pamir, Altai and Tien Shan.
The father of Russian high altitude physiology is
considered to be Nicolai Sirotinin (1897-1977), who
built up the Institute of Physiology in Kiev, mainly to
study the effects of hypoxia. His primary interest was
in acid-base balance and he attributed the symptoms
of mountain sickness to lack of carbon dioxide, as
did Angelo Mosso. Between 1930 and 1940 he organized and took part in nine high altitude expeditions.
Another very important physiologist was Z. I.
Barbashova (1910-80) who studied the effects of
hypoxia on the cells and peripheral tissues, and
showed tissue adaptation to be present.
Postwar studies were stimulated by populations
living at altitude for commercial reasons and the
growth of space science. Good tolerance to hypoxic
stress was considered an indication of the ability to
combat the generalized stress of space flight.
In 1973 a permanent medical and biological
station was opened in Terskol at the foot of Elbruz,
at about 2000 m, and research expeditions have
taken place in Tadzhikistan and Kirghizia, where
M. M. Mubrakhimov has studied indigenous populations.
In 1983 rigorous exercise tests on potential Everest
climbers revealed unsuspected cardiac abnormalities
(Gippenreiter 1983, 1993 (personal communication); Gazenko 1987).
Many workers worldwide are now active in this
field, including Japanese, French, German and
Scandinavian workers as well as those from South
America, India and Pakistan (Rivolier 1959, 1976,
Brendel and Zink 1982, Richalet 1984, Richalet et al.
1992,Uedaetfl/. 1992).

1.13
PERMANENT HIGH ALTITUDE
LABORATORIES

In 1890 Joseph Vallot built the Observatoire Vallot

on Mont Blanc (4807 m) where studies on astronomy, glaciology and, later, physiology were carried
out. Vallot used the hut until 1920. In 1983 it was
updated by ARPE (Association pour la Recherche en
Physiologic de 1'Environment) but because it is close
to the summit of Mont Blanc access on foot may be
difficult and a helicopter is often used. The first high
altitude laboratory dedicated to physiological studies
was built by the Club Alpino Italiano on Monte
Rossa (4559 m) in 1893, originally as a climbing hut
with a room for use as a laboratory used by Anglo
Mosso; a major rebuilding program was carried out
in 1977 and field studies restarted in 1983. Almost
every year since then it has been a center for studies
by Oswald Oelz, Peter Bartsch, Marco Maggiorini
and others. Among other laboratories is one on Pikes
Peak (4300 m), Colorado, USA. Earlier work was carried out in the railway station building (including
Haldane's 1911 expedition). In recent times a modern laboratory has been built and is the responsibility
of the US Army Research Institute of Environmental
Medicine at Natick, Massachusetts. This provides
excellent facilities for accommodation and physiological research. There are also facilities on Mount
Evans (4350 m) and in the Barcroft Laboratory (3800
and summit hut at 4342 m) on White Mountain in
North America. Facilities also exist at Morococha
(4550 m) and Cerro de Pasco (4331 m) in Peru. In La
Paz (3500 m) is the Institute Boliviano de Biologia de
Altura. A center for further study of cold and high
altitude is situated at Anchorage, Alaska, and a
Medical Research Center was opened at Xining on
the northeast edge of the Tibet plateau in 1984.
Studies are also being carried out in Lhasa (3658 m)
and in Leh (3500 m) in Ladakh, India. In Shanghai a
decompression chamber dedicated to long-term
studies has been constructed. In the Sola-Khumbu,
Nepal, the Ev-K2-CNR pyramid laboratory was built
at just over 5000 m at Lobuche in 1990. In order to
study large numbers of people at moderate altitude,
the Colorado Altitude Research Institute was established in 1988 at 2500 m. Both India and Pakistan are
concerned with high altitude studies as a result of
their military confrontation at about 6000 m on the
Siachen glacier in Kashmir.

20 History
Table 1.2 Important high altitude research stations

Cesar Tejos
Laboratoro Fisica cosmica Chacaltaya (near La Paz)
Ev-K2-CNR, Lobuche
Ticlio Pass
Cab. Regina Margherita
Inst. of Andean Biology, Morococha
Inst. de Biological Mina, Aquilar de la Altura
Observatoire Vallot, Mont Blanc
Mount Evans, Colorado
Summit Lab., White Mountain, California
Cerro de Pasco
Pikes Peak, Colorado
Mauna Kea, Hawaii
La Oroya
Inst. Boliviana de la Altura, La Paz
jungfraujoch

French workers are active in South America and

elsewhere. In 1991 an expedition supported by ARPE
and led by J.-P. Richalet completed a project on the
summit of an extinct volcano, Mount Sajama (6542 m)
in Bolivia. Over 21 of equipment was taken to the summit and solar cells and batteries provided electric
power. More recently a long-term decompression
chamber experiment, Operation Everest III (COMEX)
has been completed by this group in Marseilles.
The locations of high altitude research stations are
summarized in Table 1.2

1*14
STUDIES OF INDIGENOUS HIGH
ALTITUDE DWELLERS
The extraordinary high work output of high altitude
residents was emphasized by Barcroft (1925) when
describing native miners at Cerro de Pasco (4328 m)
in the Andes:
Every few minutes like a bee out of some hive . . .
someone would appear from the mouth of the
mine. He would be much out of breath, he would
take frequent pauses on the way up, but the weight
on his back would be one hundred pounds.

Possibly with his tongue in his cheek, Barcroft commented that, 'All dwellers at altitude are persons of
impaired physical and mental powers.' This drew an

Chile
Bolivia
Nepal
Peru
Italy
Peru
Argentina
France
USA
USA
Peru
USA
USA
Peru
Bolivia
Switzerland

6100
5203
5050
4700
4559
4550
4503
4356
4350
4342
4331
4300
4209
3730
3500
3476

immediate and indignant response from Carlos

Monge, a Peruvian physician:
Andean man must be physically distinct from sea
level man, requiring much further research before
one may define let alone apply the terms inferior
and superior.

Monge and his associates were stimulated to a study

of Andean high altitude populations (Monge 1948,
Hurtado 1964, Leon-Vellade and Arregui 1993).
Studies have also been carried out in Ethiopia, the
Himalayan valleys of Bhutan, and Nepal, as part of
the International Biological Programme (Baker
1978), on the Tibetan plateau (Sun 1986) and in
Lhasa. Work has also been done on Caucasian subjects in Leadville (3100 m), especially by a group
from the University of Colorado, Denver (Winslow
and Monge 1987 pp. 15-16).
Recently studies at sea level on elite Sherpas, born
and bred at high altitude, who had had considerable
experience of extreme altitude, showed that they had
high aerobic capacities of 66 mL min > kg-1 and maximum heart rates of 199 beats min"1 (Garrod et al.
1997). Sun et al. (1970) reported a V02max of
50-58 mL min' kg-1 in Tibetans born and bred at
altitude and a high V02 max was found in Andean highlanders (Vogel et a/. 1974).
The number of studies on the high altitude populations in Tibet has greatly increased in the last few
years. These studies have compared Tibetans with

Studies of indigenous high altitude dwellers 21

Han Chinese and more recently with highlanders of

South America. Differences have been found in
respect of hemoglobin concentration, arterial oxygen
saturation, pulmonary hypoxic pressor response and
susceptibility to various forms of mountain sickness.
These are reviewed in Chapter 17.
A new category of people exposed to altitude
hypoxia is those who commute to work at altitude.
These include miners in the Andes, working, for
instance, at the new Collahuasi mine (4400-4600 m)

in Chile, and scientists and technicians working on

the telescopes on Mauna Kea (4200 m) in Hawaii
(see Chapter 29).
The increasing number of national and international conferences held and societies established in
the last two decades attests to increasing interest in
the field of high altitude medicine and physiology.
The first book devoted exclusively to the history of
the subject was published in 1998 (West 1998).

2
The atmosphere
2.1
2.2

Introduction
Barometric pressure and altitude

22
23

2.3

Factors other than barometric pressure at

high altitude

30

SUMMARY

2.1

INTRODUCTION

An understanding of some of the physical principles of the atmosphere is important in high altitude
medicine and physiology. This is because most of
the problems that occur at high altitude are attributable to the hypoxia which is caused by the
decrease in barometric pressure as altitude
increases. The relationship between barometric
pressure and altitude is discussed, particularly for
regions of the world such as the Andes and
Himalayas where large numbers of people reside at
high altitude. Recent work has determined the
pressure-altitude relationship with much better
confidence than previously. Considerable confusion
has occurred in the past by assuming that the relationship follows the standard atmosphere. In fact,
the pressures are usually substantially higher at a
given altitude because the relationship between
barometric pressure and altitude is latitude dependent, and most of the high mountains of the world
are relatively near the equator. At extreme altitudes,
the variation of barometric pressure with season is
sufficient to affect human performance. This is particularly true of the summit of Mount Everest
where climbers are near the limit of tolerance to
hypoxia. Other atmospheric factors such as
temperature, humidity and solar radiation are also
important.

It has been known since the time of Paul Bert and the
publication of La Pression Barometrique (Bert 1878)
that most of the deleterious effects of high altitude on
humans are caused by hypoxia. This in turn is a
direct result of the reduction in atmospheric pressure. Yet in spite of the fact that we celebrated the
centennial of Bert's book several years ago, there is
still confusion in the minds of some physicians and
physiologists about the relationship between barometric pressure and altitude, particularly at extreme
heights. For example, some environmental physiologists are still surprised to learn that the barometric
pressure at the summit of Mount Everest is considerably higher than that predicted by the standard
pressure-altitude tables used by the aviation industry, and that humans can reach the summit without
supplementary oxygen only because the tables are
inapplicable.
Although most of the undesirable effects of high
altitude are due to hypoxia, under some circumstances additional deterioration results from cold,
dehydration, solar radiation, and even ionizing radiation. However, most of these hazards of the environment can be avoided by proper clothing or
shelter. Only hypoxia is unavoidable unless, of
course, supplementary oxygen is available. The low
barometric pressure in itself has no physiological

Barometric pressure and altitude 23

sequelae unless the decompression is rapid, for

example in the case of the explosive decompression
that occurs when a window fails in a pressurized aircraft. Rapid decompression causes so-called barotrauma as a result of the very rapid enlargement of
airspaces within the body including the lungs and
middle ear cavity. Such accidents can also occur in
ascent from deep diving, but are not considered here.
That low pressure per se is innocuous was not
always realized. Indeed, early theories of mountain
sickness included a number of exotic explanations
based on the reduced pressure itself (Bert 1878,
pp. 342-7 in 1943 translation). One was weakening
of the coxofemoral articulation; it was thought that
barometric pressure was an important factor in
pressing the head of the femur into its socket and
that, at high altitudes, the necessary increase in
action of the neighboring muscles resulted in fatigue.
Another hypothesis was that superficial blood vessels
would dilate and rupture if the barometric pressure
which normally supported them was reduced.
Indeed, modern day medical students occasionally
raise issues of this kind when they are first introduced to high altitude physiology. A further theory
was that distension of intestinal gas would interfere
with the action of the diaphragm and also impede
venous return to the heart. All these theories neglect
the fact that, when humans ascend to high altitude,
all the hydrostatic pressures in the body fall together.
In other words, although the pressure outside the
superficial blood vessels falls, the pressure inside the
vessels falls to the same extent and therefore the pressure differences across the vessels are unchanged.

2.2
BAROMETRIC PRESSURE AND
ALTITUDE

2.2*1

Historical

The notion that air has weight and therefore exerts a

pressure at the surface of the Earth evaded the
ancient Greeks and had to wait until the Renaissance.
Galileo (1638) was well aware of the force associated
with a vacuum and therefore the effort required to
'break' it, but he thought of this in the context of a
force required to break a copper wire by stretching it,
that is, the cohesive forces within the substance of the
wire. In 1647, Otto von Guericke provided a graphic

demonstration of the forces associated with a vacuum when he showed that teams of horses could not
separate two carefully fitting hemispheres from
which the air had been pumped. But it was left to
Galileo's pupil Torricelli to realize that the force of a
vacuum is due to the weight of the atmosphere. In his
memorable letter addressed to Michelangelo Ricci in
1644 he wrote, 'We live submerged at the bottom of
an ocean of the element air, which by unquestioned
experiments is known to have weight' (Torricelli
1644). How simple and striking this is. Moreover,
Torricelli wondered whether the air pressure became
less on the tops of high mountains where the air
'begins to be distinctly rare ...' as he put it. Torricelli
is credited with making the first mercury barometer,
though barometers filled with other liquids had
apparently been constructed previously, for example
by Caspar Berti. These were unsatisfactory because of
the effect of the vapor pressure of the liquid.
The Jesuit priest Joseph de Acosta, who accompanied the early Spanish explorers in Peru, gave his
dramatic description of acute mountain sickness as
early as 1590 (de Acosta 1590). This included the
inspired guess that the deleterious effects of high altitude were caused by the thinness of the air. However,
the landmark experiment took place in 1648 when
the French philosopher and mathematician Blaise
Pascal suggested that his brother-in-law, F. Perier,
take a barometer to the top of the Puy de Dome
(1463 m) in central France to see whether the pressure fell (Pascal 1648). The results were communicated to Pascal in a delightful letter by Perier in which
he described how the level of the mercury barometer
fell some three pouces (about 75 mm) during the
ascent of '500 fathoms' of altitude (probably about
900 m). The experiment had elaborate controls. For
example, the Reverend Father Chastin, 'a man as
pious as he is capable', stood guard over one barometer in the town of Clermont while Perier and a number of observers (including clerics, counselors, and a
doctor of medicine) took another to the top of the
mountain. On returning, it was found that the first
barometer had not changed, and Perier even checked
it again by filling it with the same mercury that he
had taken up the mountain. Another observation
was made the next day on the top of a high church
tower in Clermont, and this also showed a fall in
pressure, though of much smaller extent.
A few years later, Robert Boyle carried out experiments with the newly invented air pump and wrote

24 The atmosphere

his influential book New Experiments PhysicoMechanicall Touching the Spring of the Air, and its
Effects. In the second edition of this book published
in 1662 he formulated his famous law, which states
that gas volume and pressure are inversely related (at
constant temperature) (Boyle 1662).
An influential analysis of the relationships
between altitude and barometric pressure was made
by Zuntz et al. in 1906. They pointed out the important effect of temperature on the pressure-altitude
relationship noting that, on a fine warm day, the
upcurrents carry air to high altitudes and thus
increase the sea level barometric pressure. Indeed,
this is the basis for weather prediction based on barometric pressure.
Zuntz et al. (1906, pp. 37-9) gave the following
logarithmic relationship for determining barometric
pressure at any altitude:

where h is the altitude difference in meters, t is the

mean temperature (C) of the air column of height
h, B is the barometric pressure (mmHg) at the
lower altitude, and b is the barometric pressure at
the higher altitude. Note that this expression
implies that the higher the mean temperature, the
less rapidly does barometric pressure decrease with
altitude. In addition, if temperature were constant,
log b would be proportional to negative altitude,
that is, the pressure would decrease exponentially as
altitude increased. Zuntz et al. cite Hann's Lehrbuch
der Meteorologie where the pressure-altitude relationship is given in a slightly different form (Hann
1901).
Zuntz et a/.'s expression was used by FitzGerald
(1913) in her study of alveolar Pcc,2 and hemoglobin
concentration in residents of various altitudes in the
Colorado mountains during the Anglo-American
Pikes Peak expedition of 1911. She showed that barometric pressures calculated from the Zuntz formula
agreed closely with pressures observed in the mountains when a sea level pressure of 760 mm Hg and a
mean temperature of the air column of+ 15 C were
assumed. Kellas (1917) used the same expression to
predict barometric pressures in the Himalayan
ranges, obtaining a value of 251 mm Hg for the summit of Mount Everest, assuming a mean temperature
of 0 C. This was almost the same as the pressure of

248 mm Hg given by Bert (Bert 1878, Appendix 1) in

contrast to the erroneously low values used 70 years
after Bert because of the inappropriate application of
the standard atmosphere (section 2.2.3). However, a
major difficulty with the use of the Zuntz formula is
the sensitivity of the calculated pressure to temperature and the fact that the mean temperature of the air
column is not accurately known. For example, the
barometric pressure on the summit of Mount
Everest was calculated by Kellas to be 267 mm Hg for
a mean temperature of + 15 C, but only 251 mm Hg
for a mean temperature of 0 C.
2*2*2

Physical principles

Barometric pressure decreases with altitude because

the higher we go, the less atmosphere there is above
us pressing down by virtue of its weight. If the
atmosphere were incompressible, as is very nearly
the case in a liquid, barometric pressure would
decrease linearly with altitude, just as it does in a
liquid. However, because the weight of the upper
atmosphere compresses the lower gas, barometric
pressure decreases more rapidly with height near
the Earth's surface. If temperature were constant,
the decrease in pressure would be exponential with
respect to altitude, but because the temperature
decreases as we go higher (at least, in the troposphere), the pressure falls more rapidly than the
exponential law predicts.
The relationships between pressure, volume and
temperature in a gas are governed by simple laws.
These derive from the kinetic theory of gases which
states that the molecules of a gas are in continuous
random motion, and are only deflected from their
course by collision with other molecules, or with the
walls of a container. When they strike the walls and
rebound, the resulting bombardment results in a
pressure. The magnitude of the pressure depends on
the number of molecules present, their mass and
their speed.
Boyle's law states that, at constant temperature,
the pressure (P) of a given mass of gas is inversely
proportional to its volume (V), or
PV = constant (temperature constant)
This can be explained by the fact that as the molecules are brought closer together (smaller volume), the rate of bombardment on a unit surface
increases (greater pressure).

Barometric pressure and altitude 25

Charles' law states that at constant pressure, the

volume of a gas is proportional to its absolute
temperature (T), or
VIT- constant (pressure constant)
The explanation is that a rise in temperature
increases the speed and therefore the momentum
of the molecules, thus increasing their force of
bombardment on the container.
Another form of Charles' law states that at constant volume, the pressure is proportional to
absolute temperature. (Note that absolute temperature is obtained by adding 273 to the Celsius
temperature. Thus 37 C = 310 K.)
The ideal gas law combines the above laws thus:
PV=nRT
where n is the number of gram molecules of the
gas and R is the 'gas constant'. When the units
employed are mm Hg, liters and kelvin, then R =
62.4. Real gases deviate from ideal gas behavior to
some extent under certain conditions because of
intermolecular forces.
Dalton's law states that each gas in a mixture
exerts a pressure according to its own concentration, independently of the other gases present.
That is, each component behaves as though it
were present alone. The pressure of each gas is
referred to as its partial pressure or tension (now
obsolete). The total pressure is the sum of the partial pressures of all gases present. In symbols:
P* = PF*
where Px is the partial pressure of gas x, P is the
total pressure and Fx is the fractional concentration of gas x. For example, if half the gas is oxygen,
Fo2 0.5. The fractional concentration always
refers to dry gas.
The kinetic theory of gases explains their diffusion in the gas phase. Because of their random
motion, gas molecules tend to distribute themselves uniformly throughout any available space
until the partial pressure is the same everywhere.
Light gases diffuse faster than heavy gases because
the mean velocity of the molecules is higher. The
kinetic theory of gases states that the kinetic
energy (0.5 mv2} of all gases is the same at a given
temperature and pressure. From this it follows
that the rate of diffusion of a gas is inversely proportional to the square root of its density
(Graham's law).
On the basis of different diffusion rates, one might

expect that very light gases such as helium would separate and be lost from the upper atmosphere. This
does happen to some extent at extreme altitudes.
However, at the altitudes of interest to us, say up to
10 km, convective mixing maintains the composition
of the atmosphere constant.
Vertically, the atmosphere can be divided on the
basis of temperature variations into the troposphere,
the stratosphere and regions above that. The troposphere is the region where all the weather phenomena take place and is the only region of interest to
high altitude medicine. Here, the temperature
decreases approximately linearly with altitude until a
low of about -60 C is reached. The troposphere
extends to an altitude of about 19 km at the equator
but only to about 9 km at the poles. The average
upper limit is about 10 km.
Above the troposphere is the stratosphere where
the temperature remains nearly constant at about
-60 C for some 10-12 km of altitude. The interface
between the troposphere and stratosphere is known
as the tropopause.
Beyond the stratosphere, temperatures again vary
with altitude. One of the important components of
this region is the ionosphere where the degree of ionization of the molecules makes short-wave radio
propagation possible.

2.23

Standard atmosphere

With the development of the aviation industry in the

1920s it became necessary to develop a barometric
pressure-altitude relationship which could be universally accepted for calibrating altimeters, low pressure chambers and other devices. Although it had
been recognized for many years that the relationship
between pressure and altitude was temperature
dependent and, as a result, latitude dependent, there
were clear advantages in having a model atmosphere
which applied approximately to mean conditions
over the surface of the Earth. This is often referred to
as the ICAO standard atmosphere (1964) or the US
standard atmosphere (NOAA 1976). These two are
identical up to altitudes of interest to us.
The assumptions of the standard atmosphere are a
sea level pressure of 760 mm Hg, sea level temperature of +15 C and a linear decrease in temperature
with altitude (lapse rate) of 6.5 C km"1 up to an altitude of 11 km (Table 2.1). Haldane and Priestley

26 The atmosphere

(1935, p. 323) gave the following expression for the

pressure-altitude relationship of the standard
atmosphere in the second edition of their textbook
Respiration:

where P0 and P are the pressures in mm Hg at sea

level and high altitude respectively, and H is the
height in thousands of feet. A more rigorous description is given in the Manual of the ICAO Standard
Atmosphere (1964).
It should be emphasized that this model atmosphere was never meant to be used to predict the
actual barometric pressure at a particular location.
Rather it was developed as a model of more or less
average conditions within the troposphere with full
recognition that there would be local variations
caused by latitude and other factors. Nevertheless,
the standard atmosphere has assumed some importance in respiratory physiology because it is universally used as the standard for altimeter calibrations,
and it has frequently been inappropriately used to
predict the pressure at various specific points of the
Earth's surface, particularly on high mountains.
Haldane and Priestley (1935) clearly understood
that the standard atmosphere predicted barometric
pressures considerably lower than those given by the

expression of Zuntz et al. (1906), which had been

shown by FitzGerald to predict accurately pressures
in the Colorado mountains when a mean air column
temperature of+ 15 C was assumed.
Nevertheless, some physiologists have used the
standard atmosphere for predicting the pressure at
great altitudes, for example on Mount Everest
(Houston and Riley 1947, Riley and Houston
1950-1, Rahn and Fenn 1955, Houston et al. 1987).
The barometric pressure calculated in this way for
the Everest summit (altitude 8848 m) is 236 mm Hg,
which is far too low. In retrospect, one of the reasons
for the indiscriminate use of the standard atmosphere was undoubtedly its very frequent employment in low pressure chambers during the very
fertile period of research on respiratory physiology
during World War II.

2.2.4 Variation of barometric pressure

with latitude
The limited applicability of the standard atmosphere
is further clarified when we look at the relationship
between barometric pressure and altitude for different latitudes (Figure 2.1). This shows that the barometric pressure at the Earth's surface and at an
altitude of 24 km is essentially independent of latitude. However, in the altitude range of about
6-16 km, there is a pronounced bulge in the

Table 2.1 Barometric pressures (in mm Hg) from the standard atmosphere (ICAO 1964) and a
model atmosphere (West 1996): the latter is a better fit for most sites where high altitude
physiology and medicine are studied

3281
6562
9843
13123
16404
19685
22966
26247
29528
32810

2
3
4
5
6
7
8
9
10
1

760
674
596
526
462
405
354
308
267
231
199

The P02 of moist inspired gas is 0.2094 (PB - 47).

149
131
115
100
87
75
64
54
46
38
31

760
679
604
537
475
420
369
324
284
247
215

149
132
117
103
90
78
67
58
50
42
35

Barometric pressure and altitude 27

2*2.5 Variation of barometric pressure

with season

Figure 2.1 Increase of barometric pressure near the equator at

various altitudes in both summer and winter. Vertical axis shows
the pressure increasing upwards according to the scale on the
right. The numbers on the left show the barometric pressures at
the poles for various altitudes; the altitude of Mount Everest is
8848 m. (From Brunt 1952.)

barometric pressure near the equator both in winter

and summer. Since the latitude of Mount Everest is
28N, the pressure at its summit (8848 m) is considerably higher than would be the case for a hypothetical mountain of the same altitude near one of the
poles.
The cause of the bulge in barometric pressure near
the equator is a very large mass of very cold air in the
stratosphere above the equator (Brunt 1952, p. 379).
In fact, paradoxically, the coldest air in the atmosphere is above the equator. This is brought about by
a combination of complex radiation and convective
phenomena. Another corollary of the same phenomenon is that the height of the tropopause is much
greater near the equator than near the poles. These
latitude-dependent variations of pressure are of great
physiological significance for anyone attempting to
climb Mount Everest without supplementary oxygen
because they result in a barometric pressure on the
Everest summit which is considerably higher than
that predicted from the model atmosphere.

Not only does barometric pressure alter with latitude, but there are marked variations according to
the month of the year. For example, Figure 2.2 shows
the mean monthly pressures for an altitude of
8848 m as obtained from radiosonde balloons
released from New Delhi, India, over a period of
15 years. Delhi has about the same latitude as Everest.
Note that the mean pressures were lowest in the winter months of January and February (243.0 and
243.7 mm Hg, respectively) and highest in the summer months of July and August (254.5 mm Hg for
both months). The monthly standard deviation
showed a range of 0.65 mm Hg (July) to 1.66 mm Hg
(December). The daily standard deviation was as low
as 1.54 in the summer and as high as 2.92 in the winter. The standard deviation shown on Figure 2.2 is
the mean of the monthly standard deviation for the
12 months of the year.
The single measurement of barometric pressure
(253.0 mmHg) made by Pizzo on the summit of
Mount Everest on 24 October 1981 (West et al.
1983a) is also shown on Figure 2.2. This was
4.3 mm Hg higher than that predicted from the data
shown in Figure 2.1, which is twice the daily standard
deviation of barometric pressure for the month of

Figure 2.2 Mean monthly pressures for 8848 m altitude as

obtained from weather balloons released from New Delhi, India.
Note the increase during the summer months. The mean monthly
standard deviation (SD) is also shown. The barometric pressure
measured on the Everest summit on 24 October 1981 (*) was
unusually high for that month. (From West et al. 1983a.)

28 The atmosphere

October. It should be added that Pizzo had an exceptionally fine day for his summit climb, the temperature on the summit being measured as -9 C, much
higher than expected for that altitude (section 2.3.1).
Figure 2.3 combines the effects of latitude and
month of the year on the barometric pressure at an
altitude of 8848 m. The data are for the northern
hemisphere, and the pressures for the months of
January (midwinter), July (midsummer) and
October (preferred month for climbing in the postmonsoon period) are compared. The profile for the
month of May, which is the usual month for reaching
the summit in the pre-monsoon season, is almost the
same as that for October. The data are the means
from all longitudes (Oort and Rasmusson 1971). The
data clearly show the marked effects of both latitude
and season on barometric pressure. It is interesting
that in midsummer the pressure reaches a maximum
near the latitude of Mount Everest (2835"N).
Figure 2.3 shows that if Mount Everest was at the latitude of Mount McKinley (63N), the pressure on
the summit would be very much lower.
Radiosonde balloons are released from meteorological stations all over the world twice a day, and the
resulting data on the relationship between

Figure 2.3 Barometric pressure at the altitude of Mount Everest

plotted against latitude in the northern hemisphere for
midsummer, midwinter, and the preferred month for climbing in
the post-monsoon period (October). Note the considerably lower
pressures in the winter. The arrows show the latitudes of Mount
Everest and Mount McKinley. (From West et a I. 1983a.)

barometric pressure and altitude are available from

constant pressure charts. Details on how to obtain
these are given in West (1993a). Using these data it
can be shown that the barometric pressure on the
Everest summit was 251 mm Hg when Messner and
Habeler made their first ascent without supplementary oxygen in 1978. In August 1980, Messner made
the first solo ascent without supplementary oxygen
and he was fortunate that the barometric pressure
was unusually high at 256 mm Hg; when Sherpa Ang
Rita made the first winter ascent on 22 December
1987, the barometric pressure was only 247 mm Hg.

2.2*6 Barometric pressure-altitude

relationship for locations of importance
in high altitude medicine and physiology
We have seen that the standard atmosphere generally
underestimates the pressures on high mountains,
which are of interest to people concerned with high
altitude medicine and physiology. Recently, it has
been possible to define the barometric pressurealtitude relationship in the Himalayan and Andean
ranges with some accuracy, and it transpires that the
relationship holds for many other locations where
high altitude medicine and physiology are studied.
As already stated, the first direct measurement of
barometric pressure on the Everest summit was
obtained by Pizzo in 1981 during the course of the
American Medical Research Expedition to Everest
(West eta/. 1983 a). The value was 25 3 mm Hg, as shown
on Figure 2.2. During the same expedition, careful
measurements of barometric pressure were made at
two other locations on Mount Everest where the altitudes were accurately known. These were the Base
Camp (altitude 5400 m) and at Camp 5, just above the
South Col (altitude 8050 m). These points lay very close
to a straight line on a log pressure-altitude plot and
therefore allowed the barometric pressure-altitude
relationship at very high altitudes on Mount Everest
to be accurately described for the first time (Figure 2
in West etal. 1983a). This relationship is of great physiological interest because, as discussed in Chapter 12,
the pressure near the summit is so low that the P02 is
very near the limit for human survival.
More recently, additional measurements have
been made at very high altitudes on Mount Everest
(West 1999a). Another direct measurement was
made on the summit in May 1997 and this agreed

Barometric pressure and altitude 29

within 1 mmHg of Pizzo's measurement of

253 mm Hg. In addition, a large number of measurements were reported from a barometer that telemetered information from the South Col (altitude
7986 m). When these points were added to those
obtained during the 1981 expedition (Figure 2.4),
they greatly increase our confidence in the barometric pressure-altitude relationship.
Two other pieces of data have recently come to
light. Charles Corfield made a single measurement of
the barometric pressure on the Everest summit at 10
a.m. on 5 May 1999. He used a Kollsman aneroid
barometer and the value was 253 mm Hg (personal
communication). The air temperature was -18C,
and this had been shown not to affect the calibration
of the barometer. The other data point comes from
measurements made on the South Col by the Italian
Ev-K2-CNR program. They reported 52 measurements of barometric pressure on 29 and 30
September and 1 October 1992 (personal communication). The mean value was 383.0 mbar
(287 mm Hg). This is the same pressure as that found
by the MIT group in August 1997 (West 1999a).
These two additional pieces of data fit extremely well
with the other measurements listed above.

2.2.7

Model atmosphere equation

It is now possible to provide a barometric pressurealtitude relationship that accurately predicts the
pressure at most locations of interest to high altitude
medicine and physiology (West 1996a). The data are
shown in Figure 2.5. The prediction is particularly
good if the locations lie within 30 of the equator,
and especially if the pressure is measured in the summer months. Since many studies of high altitude
medicine and physiology are carried out in locations
and times that fulfill these criteria, the relationship is
very useful in practice. The equation of the line is
PB = exp (6.63268- 0.1112/J-0.00149/72)

where PB is the barometric presssure (in mm Hg) and

h is the altitude in kilometers. This has been called
the model atmosphere equation, and is useful for

Figure 2.5 Barometric pressure-altitude relationship

corresponding to the model atmosphere equation. Note that it
predicts the altitudes of many locations of interest in high altitude
medicine and physiology very well. The lower line shows the
standard atmosphere which predicts pressures that are too low. The
locations and measured pressures are as follows: 1) Collahuasi
Figure 2.4 Barometric pressure-altitude relationship for Mount
Everest. The circles show data from the 1981 American Medical
Research Expedition to Everest. The cross at the summit altitude

mine, Chile, 438 mm Hg; 2) Aucanquilcha mine, Chile, 372 mm Hg;

3) Vallot observatory, France, 452 mm Hg; 4) Capanna Margherita,
Italy, 440 mm Hg; 5) Mount Everest Base Camp, Nepal, 400 mm Hg;

(8848 m) is from the 1997 NOVA expedition. The cross at an

6) Mount Everest South Col, 284 mm Hg; 7) Mount Everest summit,

altitude of 7986 m is from measurements made by the

253 mm Hg; 8) Cerro de Pasco, Peru, 458 mm Hg; 9) Morococha,

Massachusetts Institute of Technology in 1998. The standard

Peru, 446 mm Hg; 10) Lhasa, Tibet, 493 mm Hg; 11) Crooked Creek,

deviations are too small to show on the graph. The line corresponds

California, 530 mm Hg; 12) Barcroft laboratory, California,

to the model atmosphere equation: PB - exp (6.63268 -0.1112h-

483 mm Hg; 13) Pikes Peak, Colorado, 462 mm Hg; 14) White

0.00149h2) where h is in kilometers. (From West 1999a.)

Mountain summit, California, 455 mm Hg. (From West 1996a.)

30 The atmosphere

theoretical calculations in high altitude physiology

such as predicting the effects of oxygen enrichment
at different altitudes.

2.2*8 Barometric pressure and

inspired P02
As we have seen, the composition of the atmosphere
is constant up to altitudes well above those of medical interest so it is safe to assume that the concentration of oxygen in dry air is approximately 20.94 per
cent. However, the effects of water vapor on the
inspired P02 become increasingly important at higher
altitudes.
When air is inhaled into the upper bronchial tree,
it is warmed and moistened and becomes saturated
with vapor at the prevailing temperature. The water
vapor pressure at 37 C is 47 mm Hg and this, of
course, is independent of altitude. Thus the P02 of
moist inspired gas is given by the expression

where PB is barometric pressure.

This equation shows how much more important
water vapor pressure becomes at very high altitudes.
For example, at sea level, the water vapor pressure at
37 C is only 6 per cent of the total barometric pressure. However, on the summit of Mount Everest,
where the barometric pressure is about 250 mm Hg,
the water vapor pressure is nearly 19 per cent of the
total pressure, and the inspired P02 is correspondingly further reduced (see Table 2.1).
It has been pointed out from time to time that a
relatively small reduction in body temperature at
extreme altitude would confer a substantial increase
in inspired P0r For example, if the body temperature fell to 35 C where the water vapor is
42 mm Hg, the P02 of moist inspired gas would be
increased from 42.5 to 43.5 mmHg. This increase
of 1 mm Hg would be beneficial because the arterial
Po would increase by approximately the same
extent, and since the oxygen dissociation curve is
very steep at this point, there would be an appreciable gain in arterial oxygen concentration. However,
there is no evidence that body temperature falls at
extreme altitude. Nor is it reasonable to assume that
the temperature in the alveoli where gas exchange
takes place would be significantly less than the body
core temperature.

2*2*9 Physiological significance of

barometric pressure at high altitude
Since the barometric pressure directly determines the
inspired P02, it is clear that the variations of barometric pressure with latitude and season, as
described in sections 2.2.4 and 2.2.5, will affect the
degree of hypoxemia in the body. For example, a
climber on Mount McKinley in Alaska, which is situated at a latitude of 63N, will be exposed to a considerably lower barometric pressure on the summit
than would be the case for a mountain of the same
height located in the tropics (see Figure 2.3).
The variations of barometric pressure with latitude and season become particularly significant from
a physiological point of view at extreme altitudes
such as near the summit of Mount Everest. For
example, it has been shown that if the pressure on the
Everest summit conformed to the standard atmosphere, it would be impossible to climb the mountain
without supplementary oxygen (West 1983). In
addition, the variation of barometric pressure with
month of the year shown in Figure 2.2 indicates that
it would be considerably more difficult to reach the
summit without supplementary oxygen in the winter
as a result of the reduced inspired P02, quite apart
from the obvious difficulties of lower temperatures
and high winds. Although there have now been many
ascents of Everest without supplementary oxygen in
the pre- and post-monsoon seasons, only one person
has made a winter ascent without supplementary
oxygen: Sherpa Ang Rita on 22 December 1987. This
topic is considered in more detail in Chapter 11.

23
FACTORS OTHER THAN
BAROMETRIC PRESSURE AT HIGH
ALTITUDE

2*3*1

Temperature

Temperature falls with increasing altitude at the rate

of about 1C for every 150 m. This lapse rate is essentially independent of latitude. The consequence is
that on a very high mountain, such as Mount
Everest, the average temperature near the summit is
predicted to be about -40 C. Most climbers choose
the warmer months of the year. In May, a temperature of-27 C was measured at an altitude of 8500 m

Factors other than barometric pressure at high altitude 31

on Everest (Pugh 1957), although Pizzo obtained a

temperature of -9 C on the summit in October
(West et al. 1983a). In the winter the temperatures
are much lower. However, even then they do not
approach the extremely low temperatures seen in
northern Canada or Siberia during midwinter.
More important than temperature per se is the
wind chill factor. Wind velocities on Himalayan
peaks have often been estimated to be in excess of
150 km h"1, though few measurements have been
made. Such high winds result in extremely severe
chill factors at low temperatures and can make
climbing impossible. Cold injury is common in the
mountains and is discussed in Chapters 25 and 26.

23.2

Humidity

Absolute humidity is the amount of water vapor per

unit volume of gas at the prevailing temperature.
This value is extremely low at high altitude because
the water vapor pressure is so depressed at the
reduced temperature. Thus even if the air is fully
saturated with water vapor, the actual amount will
be very small. For example, the water vapor pressure at +20 C is 17 mmHg but only 1 mmHg at
-20 C.
Relative humidity is a measure of the amount of
water vapor in the air as a percentage of the amount
which could be contained at the prevailing temperature. This value may be low, normal or high at altitude. The disparity between absolute and relative
humidities is explained by the fact that even saturated air is unable to contain much water vapor
because of the very low temperature. If this air is
warmed without allowing additional water vapor to
form, its relative humidity falls.
The very low absolute humidity at high altitude
frequently causes dehydration. First, the insensible
water loss caused by ventilation is great because of
the dryness of the inspired air. In addition, the levels
of ventilation may be extremely high, especially on
exercise (Chapter 11), and this increases water loss.
For example, near the summit of Mount Everest, the
total ventilation is increased some five-fold compared with sea level for the same level of activity.
Pugh (1964b) found that during exercise at 5500 m
altitude, the rate of fluid loss from the lungs alone
was about 2.9 g water per 100 L of ventilation (body
temperature and pressure, saturated with water

vapor, or BTPS). This is equivalent to about 200 mL

of water per hour for moderate exercise.
There is evidence that the dehydration resulting
from these rapid fluid losses does not produce as
strong a sensation of thirst as at sea level. As a
result, climbers find it is necessary to drink large
quantities of fluids at high altitude to remain
hydrated even though they have little desire to do
so. For men climbing 7 h a day at altitudes over
6000 m, 3-4 L of fluid are required in order to
maintain a urine output of 1.5 L day1 (Pugh
1964b). Even so, it appears that people living at
very high altitude are in a state of chronic volume
depletion. In a group of subjects living at an altitude of 6300 m during the American Medical
Research Expedition to Everest, serum osmolality
was significantly increased compared with sea level
despite the fact that ample fluids were available and
the lifestyle in terms of exercise and diet was not
exceptional (Blume et al. 1984).

233

Solar radiation

The intensity of solar radiation increases markedly at

high altitude for two reasons. First, the much thinner
atmosphere absorbs less of the sun's rays, especially
those of short wavelength in the near ultraviolet
region of the spectrum. Second, reflection of the sun
from snow greatly increases radiation exposure.
The reduced density of the air causes an increase
in incident solar radiation of up to 100 per cent at
an altitude of 4000 m compared with sea level
(Elterman 1964). The fact that mountain air is so
dry is another important factor because water vapor
in the atmosphere absorbs substantial amounts of
solar radiation.
The efficiency with which the ground reflects
solar radiation is known as its albedo. This varies
from less than 20 per cent at sea level to up to 90
per cent in the presence of snow at great altitudes
(Buettner 1969). Mountaineers are familiar with the
extreme intensity of solar radiation, especially on a
glacier in a valley between two mountains. Here the
sunlight is reflected from both sides as well as from
the snow or ice on the glacier and the heat can be
very oppressive despite the great altitude. A consequence of this is the extreme variation in temperature which has been noted in camps under these
conditions.

32 The atmosphere

23*4

Ionizing radiation

The intensity of cosmic radiation increases at high

altitude because there is less of the Earth's atmosphere to absorb the rays as they enter from space.
This is the reason why cosmic radiation laboratories are often located on high mountains. It has
been shown that, at an altitude of 3000 m, the
increased cosmic radiation results in an increased

radiation dose to a human being of approximately

70 mrad (0.0007 Gy) per year. This should be considered in relation to the normal background radiation dose from all sources of 50-200 mrad
(0.0005-0.002 Gy) per year. The increased ionizing
radiation of high altitude has been cited as one of
the factors causing acute mountain sickness (Bert
1878), but there is no scientific basis for this
assertion.

3
Geography and the human response to altitude
3.1

Introduction

33

3.6

Houses and shelter

3.2
3.3
3.4
3.5

Terrain
Climate
Economics
Load carrying

36

3.7

36
38
39

3.8
3.9

Clothing
Population

SUMMARY
The highland areas of the world support considerable populations. The climate is harsh and methods
of cultivation have to be adapted to the terrain.
Terracing has been brought to a fine art in the
mountain regions, although the South American
altiplano and the Tibetan plateau allow normal
methods of cultivation. Animal husbandry and
mining are important, and tourism is becoming
increasingly popular.
Mountains often form boundaries between
cultures. Border peoples have developed a physique
that enables them to survive under severe conditions
of cold and hypoxia. Commerce in high valleys
without roads depends on porters and without their
remarkable capacity to carry loads the economy
would remain static. Acclimatization to hypoxia is
complex and far reaching and depends on the severity
and rate at which oxygen lack is imposed. Local cold
tolerance but not general cold acclimatization occurs,
and protection is mainly by cultural methods.

3.1

INTRODUCTION

Although the expression 'high altitude' has no

precise definition, the majority of individuals have

Human response to cold and altitude

41
41
42
43

certain clinical, physiological, anatomical and biochemical changes which occur at levels above
3000 m. Individual variation is, however, considerable and some people are affected at levels as low as
2000 m. For sea level visitors, an altitude of
4600-4900 m represents the highest acceptable level
for permanent habitation; for high altitude residents
5800-6000 m is the highest so far recorded (West
1986a). At greater altitudes physical and mental
deterioration occurs and permanent habitation is
not possible (section 3.8.2, Chapter 17). In South
America archaeological sites have been found at
6271 m on Llullaillaco, but there is no evidence that
these were permanent dwellings.
The main areas of the world above 3000 m are:

the Tibetan plateau

the Himalayan range and its valleys
the Tien Shan and Pamir
the mountain ranges of east Turkey, Iran,
Afghanistan and Pakistan
the Rocky Mountains and Sierra Nevada of the
USA and Canada
the Sierra Madre of Mexico
the Andes of South America
the European Alps
the Pyrenees between Spain and France
the Atlas Mountains of North Africa
the Ethiopian highlands

34 Geography and the human response to altitude

the mountains of East and South Africa

the plateau and mountains of Antarctica
parts of New Guinea and other small regions
such as Hawaii, Tenerife and New Zealand.
The European Alps do not support a large high
altitude population, but the region is vitally important because of its position at the crossroads of
Europe and because modern investigation into all
aspects of mountain science originated there.
The three main regions that support large
populations are the Tibetan plateau and Himalayan
valleys, the Andes of South America and the
Ethiopian Highlands. Although the plateau and
peaks of Antarctica are a large area of high altitude
there is no indigenous population.

The native population was neither static nor

homogenous, but it was the Romans who established
the main framework of communication in this
region. However, their roads had little impact on the
essential pasturalism of the Alpine economy and the
mountains themselves were feared by the Romans as
the abode of dragons and evil forces. The people,
with their susceptibility to goitre, were not much
admired either.
It was not until the nineteenth century that
gradual easing of communications opened up the
whole region to the outside world and ignorance
turned to knowledge and understanding (Snodgrass
1993).

3.1.2
3.1.1

Himalayas and Tibetan plateau

European Alps

The early development of all branches of mountain

science resulted from the increasing ability to travel
in these inhospitable regions, due to developments in
mountaineering and skiing.
The word 'alp' is based originally on a Celtic word
meaning 'high mountain': the modern use of this
word meaning 'high pasture' dates from the Middle
Ages.
The history of the European Alps is the story of
how this region, constrained by its geographical
position and topography, became a vital and
indispensable link in the communications of the
whole of Europe.
The discovery of 'Similaun Man', some 5000 years
old, at a height of 3210 m shows that considerable
altitudes were reached by local people when crossing
from one valley to another. The deposition of gold
bracelets to propitiate the mountain gods was
common from prehistory to the Middle Ages and
many offerings have been found in the neighborhood
of the Great St Bernard Pass. Here the Roman deity
Poeninus presided over the crossing and he is commemorated in the present day name, Pennine Alps.
The century between 50 BCE and 50 CE was the first
period in which the whole of the European Alps
came into the orbit of one political system, the
Roman Empire, with communications linking Rome
via the Alpine passes with the periphery of that
empire. Many of the names used for subregions, such
as Alps Maritimae and Alps Cottiae, are still in use
today.

The Himalayas form a topographically extremely

complex region, extending 1500 miles from Nanga
Parbat (8125 m) in the west to Namcha Barwa
(7756 m) in the east. At their western extremity they
are part of a confused mass of peaks, passes and glaciers where the western Kun Lun, Karakoram, Pir
Panjal and Pamirs form an area the size of France.
The Himalayas contain the world's highest mountain, Mount Everest (8848 m), and many other peaks
over 7500 m. The main range forms the watershed
between Central Asia and India, and there are middle
ranges at intermediate altitudes. The outer
Himalayas (up to 1500 m) form foothills rising from
the plains of India.
The Tibetan plateau is an area occupied by
Tibetans, who have a well defined culture. It extends
in the south to the Himalayas and high Himalayan
valleys. To the west the plateau is demarcated by the
northward curve of the Himalayas which continues
into Kashmir, Baltistan and then to Gilgit and the
Karakoram. To the north the peaks (up to 7700 m) of
the Kun Lun range, 1500 miles long, mark off the
plateau of Tibet from Xinjiang (Chinese Turkestan);
to the east it extends to the Koko Nor or Qinghai
Lake and, further south, the valleys of Qinghai and
Sikiang and the gorge country of south-east Tibet.
The area covers about 1.5 million square miles and
is the largest and highest plateau in the world, much
of it at an altitude of 4600-4900 m. It presents an
enormous range of climate and topography. 'Every
10 li (3 miles) heaven is different.' The major climatic
contrast is between the southern side of the

Introduction 35

Himalayas and the high valleys exposed to the

summer Indian monsoon with very high rainfall,
particularly in the east, and the aridity and low
rainfall of the Tibetan plateau. The change is so
abrupt that in some passes in the eastern Himalayas,
vegetation may change from tropical to subarctic
within a few yards. .
The Tibetans believe that in the prehistoric era
their land was a large sea, Tethys, which, according to
the theory of plate tectonics, is correct. The Royal
Society/Chinese Academy of Sciences Tibet Geotraverse in 1985-6 established that the thickness of
the Tibetan plateau crust, which at 70 km is about
twice as much as normal, is due mainly to folding
and thrusting that has occurred as a result of India
colliding with Asia, rather than India moving under
Asia and elevating to a plateau (Chang et al. 1986). In
mythology, Tibetans are descended from the union
of a forest monkey and a female demon of the rocks,
with the site of the first cultivated field being at
Sothang in south-east Tibet, but other legends place
their origin further east.
The Tibetans have always regarded themselves as
living in the northern part of the world; the Indians,
however, considered the Himalayas to be the abode
of the gods and inhabited by a race of supermen
gifted with special knowledge, particularly of magic,
and this probably accounts for the popular European
belief of Tibet as a place where the immortal sages
dwell, guarding the ultimate secrets. Far from being
isolated, however, Tibetans have been subject to
influences from China, India, Central Asia and the
Middle East for many centuries (Stein 1972).
With increasing numbers of Han Chinese
immigrants there are more than 3.0 million people
living over 3000 m, and it is estimated that the
amount of this land available for agriculture is 5 per
cent. In the valleys, fields are terraced; on the plateau,
larger fields are found in sheltered areas on valley
floors, but all are threatened by snow, hail, wind and
erosion. Permanent buildings are found up to
3500 m with nomadic populations at higher levels.
Neolithic human remains have been found near
Lhasa (Ward 1990, 1991).

3.1.3

Andes of South America

The highland zone extends from Colombia in the

north to central Chile in the south, and is flanked by

an arid desert on its west, with a deeply eroded

escarpment to the east, which adjoins the Amazon
basin.
The central Andean region has three broadly
defined areas running parallel with the Pacific Ocean:
the cordillera occidentale, the altiplano, a broad
undulating plain at 4000 m in the middle, and the
cordillera orientale in the east.
The earliest archeological evidence for human
occupation dates back 20 000 years (MacNeish 1971)
and has been found at Ayacucho, Peru; at 2900 m;
other early finds are recorded in central Chile,
Venezuela and Argentina. The skeleton of a man who
lived 9500 years ago has been found at Lauricocha
(4200 m) in Peru (Hurtado 1971). The pre-Inca
civilizations were situated mainly along the Pacific
Coast and the population subsisted mainly on
seafood. Little is known of the highland population
during this period.
The Inca civilization only achieved a position of
major importance in the 100 years preceding the
Spanish invasion of 1532. Spanish settlement of
highland areas was hindered by ecological restraints
imposed by altitude and the nature of the terrain,
and, after consolidation of Spanish rule, Peru
remained under colonial domination for 300 years,
achieving independence in 1824.
Both agriculture and stock raising dominate the
subsistence economy, with the upper limit of agriculture at 4000 m and the upper limit of vegetation at
4600 m. Mining is carried out at even greater
altitudes and tourism is increasingly popular.

3.1.4

Ethiopian highlands

No well circumscribed highland zone exists. The

country is intersected by a number of rift valley
systems, establishing a connection between the
African rift valley in the south and the Red Sea. The
valley systems divide the country into three reasonably well defined regions: the western highlands,
the eastern highlands and the rift valley itself with the
lowland area.
The northern part of the western highlands, the
Amhara highlands, attains the greatest altitude
(2400-3700 m). The highest peak of Ethiopia, Ras
Dashau (4620 m), is a volcanic outcrop and Lake
Tana, the origin of the Blue Nile, lies at the center of
the region. Much of Ethiopian history centers on this

36 Geography and the human response to altitude

area, which has been settled for many centuries. It is

inhabited by the largest of Ethiopia's many
population groups, the Amharas and Tigraeans, who
are the descendants of people who came from
southern Arabia prior to 1000 BCE (Sellassie 1972).
Gondar (3000 m), in the Amhara highlands, with a
population of 100 000, became the second largest city
in Africa, and it remained the capital of Ethiopia
until the middle of the first century, when Addis
Ababa was founded.
Much of the population of Ethiopia lives above
2000 m and in the highland area two types of cultivation, by plough and by hoe, predominate. Teff, a
type of grass which produces a small seed, is grown
up to 3000 m and is the mainstay of the agricultural
economy.

3.2

TERRAIN

Although mountain country varies widely, there are

two distinct types: the high, flat, plateaux (Tibet and
the altiplano of South America) and deep valleys
(Himalayas and Andes).
Plateaux can support large populations and large
towns but they may be isolated by virtue of distance
from lowland cities, which are usually the center of
government, commerce and industry.
In mountain valleys, because flat ground is at a
premium, populations tend to be smaller, with
groups perched on slopes and ridges far from one
another. The placing of houses in sunny positions is
more difficult and isolation within the community is
common. Communications are easily severed by
land slips, avalanches and other natural disasters.
The funneling effect of valleys on wind may increase
its velocity with an ensuing stunting effect on
vegetation and trees. This also restricts the placing of
houses, as does the availability of water and the
possibility of natural disasters (Figure 3.1).

33

CLIMATE

The climate near the ground at high altitude has

several basic features. At any given latitude, seasonal
variation of monthly temperature is less at high
altitude than at sea level and, as the equator is
reached, seasonal variation virtually disappears.

Diurnal variations are considerable, and can show a

range of 30 C. This is because of high levels of longwave radiation that occur in cloudless skies during
the day and escape to clear skies at night. In overcast
conditions the diurnal variation decreases.
With increasing altitude the temperature falls.
There is no uniform value for decline although the
figure 1 C for every 150 m is usually given.
Solar radiation is an important factor in maintaining thermal balance in humans at extreme altitude.
High winds are also a feature of mountains. A gust of
231 miles/h has been recorded on Mount
Washington (1917 m) in the eastern USA.

33.1

Rainfall

In Asia, the monsoon flows from east to west

across India, cooling as it is forced to ascend by the
Himalayas. Water vapor condenses and falls as
rain, and as it passes to the west the monsoon
becomes depleted of water; the eastern Himalayas
are thus very wet, the western dry. In Darjeeling
the annual rainfall is 2000-3000 mm a year; in the
central Himalayas at Simla it is 1500 mm, but in
the west at Ladakh it is only 75 mm. The
Karakoram is arid whereas the eastern Himalayan
region is tropical.
There is also considerable north-south variation
with Palearctic species on the Tibetan plateau and
tropical species often only a few hundred yards away
to the south. This is particularly marked on some
passes in the eastern Himalayas. On the plateau,
although 'monsoon' clouds are seen on the Tangulla
range, about 700 km north of Lhasa precipitation is
small. In the deserts of the Tarim basin and Tsaidam
to the north of the Tibetan plateau, annual rainfall
maybe less than 100 mm.
In the Andes the Pacific coastal strip is desert - 'It
never rains in Lima.' Along the whole length of the
coast the cold Humboldt current cools the air above
the sea, reducing its capacity to retain moisture
which normally falls as rain. Once air passes over the
land, it is warmed again and increases its capacity to
retain moisture, making rain unlikely.
The western slopes of the Andes are dry, cacti and
eucalyptus trees flourish and only a few high
mountains are snow covered. The eastern slopes
which descend to the Amazon basin become progressively more humid and tree covered.

Climate 37

Image Not Available

Figure 3.1 Contrasting terrain and

climate at altitude, (a) Rain clouds over
the Himalayas during the monsoon
period (September). (Reproduced with
permission of the Library of the Royal
Geographical Society.) (b) The north
Tibetan plateau with the Kun Lun range
in the background.

The rainfall in the UK and Europe is influenced by

the gulf stream. Records kept between 1884 and 1901
by the observatory on the summit of Ben Nevis,
Scotland (1300 mm), the highest peak in the UK,
show that the average daily sunshine was only 2 h
and the annual rainfall was 3500 mm, as much or
more as in Darjeeling (MacPhee 1936).

33*2 Temperature
The fall in temperature globally with altitude has
been discussed in Chapter 2. However, the
temperature of mountain regions is very variable
and records of the observatory on the summit of

Ben Nevis (1300 m) between 1884 and 1901 show

that the mean temperature over these 17 years was
-0.1 C; the lowest temperature was -17 C and the
highest +19 C. On the plateau of the Cairngorms in
Scotland, which has an average height of around
1000 m, similar temperatures have been recorded
with winds gusting to over 160 km h"1 (100 mph).
In North America, Alaska and the Yukon a
number of peaks of 6000 m lie within the Arctic
Circle. Because of their latitude the barometric
pressure, and therefore alveolar P02' is lower than on
peaks of a corresponding altitude in the Himalayas,
which are at a latitude of 28N. They therefore
appear to be 'higher', with all the corresponding
dangers of mountain sickness and altitude deteriora-

38 Geography and the human response to altitude

tion (Chapter 2). Temperatures of -30 C at

5500-6000 m have been recorded, with gale force
winds, in the winter (Mills 1973b).
In the European Alps, the average temperature
was -13 C during a winter expedition up to 4000 m,
carried out over several days, in the Bernese
Oberland in Switzerland (Leuthold et al. 1975); gale
force winds were not uncommon. Temperatures on
the summit of Everest (8848 m) in winter are
probably of the order of -60 C; in summer the
average temperature would be about -20 C. Hillary
recorded a temperature of -27 C at 8500 m on
Everest at 3 a.m. on 29 May 1953, the day the first
ascent was made (Ward 1993b). On the Changthang
(the northern part of the Tibetan plateau), which has
an average height of 4900 m, there are few days when
the temperature reaches as high as 10 C and -25 C
has been recorded.
In Lhasa (3658 m) there are about 100 days a year
when the temperature is around 10 C; in summer it
may rise as high as 27 C but in the winter it falls to
-15 C.
In Antarctica, the lowest recorded temperature is
-88.2 C and the highest 15.2 C. The dangers of cold
injury, therefore, are likely to complicate accidents or
illness in mountain regions.

333

Humidity

Ambient humidity influences heat loss from the

body by evaporation and, in regions where the
humidity is high, heat regulation is more difficult. In
arid areas with a low humidity heat regulation is
easier.

33*4

Solar radiation

Although temperature falls with altitude there is

increased exposure to solar radiation (Chapter 2).
The amount of radiation absorbed by the body
depends on clothing and posture. The clear mountain air permits an increased degree of direct radiation which is enhanced by indirect radiation reflected
from the snow. The altitude of the sun is also important (Chrenko and Pugh 1961). The solar heat
absorbed depends on the type of clothing - dark
clothing absorbs more radiation than light-colored
clothing.

33*5

Ultraviolet radiation

There appears to be some increase in the level of

ultraviolet radiation at high altitude.
Snow reflects up to 90 per cent of ultraviolet
radiation, compared with 9-17 per cent reflected
from ground covered by grass (Buettner 1969), so in
snow-covered terrain the combination of direct
(incident) and reflected ultraviolet radiation is
considerable.

3.4

ECONOMICS

Most mountain communities depend on animal

husbandry and agriculture; mining is important in
some regions but more recently tourism has assumed
a greater significance.
Animal husbandry predominates in regions above
the limit of agriculture. On the Tibetan plateau, or
Changtang, which covers two-thirds of Tibet, there
are immense herds of yak, sheep and goats herded by
nomads. In the bitter climate nomadic pastoralism is
the only viable and economic way of life and this may
have started between 9000 and 10 000 years ago. The
survival of the animals depends exclusively on
natural fodder, which creates problems as the sedges
and grasses have only a short growing season
between May and September. Because there are no
areas on the plateau where grass will grow in the
winter they cannot escape the climate and, as
extensive migration would weaken the stock, only
short distances, up to 40 miles, are traversed. Each
family has a 'home base', which is sometimes a
house, and migrates to set areas whose boundaries,
though not fenced, are all well known. Here, tents
made of yak and sheep's wool are used as dwellings.
Further north camels are common (Goldstein and
Beall 1989). In the upper Himalayan valleys the
pattern is similar, with flocks spending the summer
on pastures up to 5000 m, but below the snow line; in
the winter they return to more permanent and
protected locations at 4000 m.
The llama (Lama glama) and yak (Bos grunniens)
are extremely important to the economy of the
populations of the South American altiplano, and of
Tibet and the Himalayan valleys. Both these species
show genetic adaptation to high altitude (Chapter
17).

Load carrying 39

The limiting factor in agriculture is the number of

months that the soil remains frozen; only a single
period of the year may be available for cultivation.
The type of crop may influence the size of population. Potatoes introduced into the high Himalayan
valleys of Nepal between 1850 and 1860 increased the
population of Sola Khumbu in the Everest region
from 169 households in 1836 to 596 in 1957 (FuhrerHaimendorf 1964, p. 10). Immigrants came from
Tibet over the Nangpa La, a glacier pass of 5800 m,
and, because food was more abundant, were able to
adopt the religious life and built many new
monasteries. Increasing the productivity of the land,
as well as the area under cultivation in Tibet, may
change the pattern of life near the centers of
population under the present Chinese-organized
regime. Level land may have to be manufactured in
the form of terraces, which range in size from a few
square feet to a relatively large area, which is usually
too small for pasture. Irrigation may involve
ingenious construction of water conduits from
surrounding streams. The task of building and
maintaining terraces is considerable, especially as
manure has to be carried up and placed manually.
Despite this, terracing is a marked feature of
populated mountain valleys and, as it involves
ownership and maintenance by groups rather than
individuals, the social implications are important.
High grazing pasture (alps) is also communal
pasture land and this too has social overtones.
Mining, which is often carried out above the
pasture level or in rocky terrain, may involve the
building of special towns and roads. Frisancho
(1988) suggests that one reason for the relatively high
hemoglobin concentration observed in Andean high
altitude populations as opposed to those in the
Himalayas is that miners (among whom respiratory
disease is common) were included in some Andean
samples. In Tibet gold mining has been carried on for
centuries, often at 5000 m. However, shallow
trenches were used and no deep mines were worked.
Recently a gold mine has been established at 4500 m
in northern Chile, and other mines are being opened
at comparable altitudes.
Tourism, particularly skiing, may involve developing an area which has no natural amenities except
good snow fields and glaciers. In 1992, 16 000
tourists visited the Everest region; as a result pollution, often in the form of nonbiodegradable rubbish,
is a considerable problem.

Isolation, together with unexplained natural

catastrophes, contributes to the undoubted tendency
that mountain people have towards the religious life.
Once this is established, the disinclination to accept
change, so prevalent in religious-dominated communities, prevents the development of the communities, which then become easy prey to their more
technically advanced neighbors.
3.5

LOAD CARRYING

Loads are carried by all who visit mountainous

regions. In the valleys of the Himalayas professional
porters carry much of the merchandise and the
economy depends on them, together with yak and
mule transport (Figure 3.2).
Observations by Pugh in 1952 and 1953 on the
march in to Everest (Pugh 1955b) suggest that loads
of 40-50 kg, with an addition of 10 kg personal
baggage, are carried routinely by porters for 10-12 h
over 10-12 miles each day. Often ascents and descents
of 1000-1200 m are made, with loads of tea or paper
weighing over 60 kg occasionally being carried.
As the body weight of porters is usually 45-60 kg,
and the average height just over 150 cm, each porter
carries his own weight in merchandise.
Where possible, loads are carried in a conical, light
but strong, wicker basket, 22 cm x 30 cm at the base
and 50 cm X 70 cm at the top, with a height of 60 cm.
Larger sizes are available for carrying bulky loads
such as leaf mould. Loads are supported by a strap
passing over the forehead and under the lower end of
the basket. When in position the upper end of the
basket is level with the top of the porter's head. The
center of gravity therefore is as close as possible to a
vertical line passing through the center of the pelvis,
thus reducing the angular momentum. The advantage of the head band is that it allows direct transmission of the load to the vertebral column, with
muscles being used for balancing rather than
support, as when shoulder straps are used. This
method of carrying has to be learnt as a child, and the
neck muscles in all such Himalayan porters are
extremely well developed.
Marching technique depends on the weight of the
load. With loads of 50 kg, stops are made every
2-3 min, with rests lasting 0.5-1.0 min after a
distance of 70-250 m has been covered, depending
on the gradient. With lighter loads, rests for 2-3 min

40 Geography and the human response to altitude

Image Not Available

Figure 3.2 Load carrying in the

Himalayas, (a) Yaks carrying
supplies over the Nanga La (5800 m).
(Reproduced with permission of the
Library of the Royal Geographical
Society.) (b) Nepalese porters
carrying people and supplies.

every 10 min are normal. Longer pauses are made

every hour.
During rests, the loads are supported on a T-stick
about 1 m long, and the porter does not sit down.
When longer rests are taken, loads are placed on the
top of stone walls conveniently placed beside the
track, usually in the shade of a large tree.
Heart rate in ascending porters varies between 140
and 160 beats min"1: on the level between 100 and
124 beats min"1 and downhill between 80 and 104
beats min"1.
At about 3700 m, porter loads are reduced to 25 kg
(gross weight 35 kg) which are carried to 5700 m.
Exhaustion, when it occurs, is due to overwork; that
is, not enough rest days. Few porters have any

interest in climbing mountains and so tend to give

up when the effects of hypoxia appear.
With high altitude Sherpas, load carrying ability is
considerable. Without supplementary oxygen on
Everest in 1933 eight porters carried loads weighing
10-15 kg to an altitude of 8300 m, as they did on the
Swiss Everest Expedition in 1952.
Low altitude porters carry their own food, eating
tsampa or ata, which is made into a paste or dough,
three times a day. Four seers (4 kg) of tsampa is the
standard ration for each man for 3.5 days, equivalent
to 3500 kcal (14.6 kj) man"1 day"1.
Mountaineers also carry considerable loads to
high altitude but use shoulder straps, climb more
slowly and stop less frequently.

Clothing 41

3.6

HOUSES AND SHELTER

Cultural mechanisms that provide a comfortable

microclimate and reduce heat loss have been
developed in all high altitude communities. The ideal
house should be draught free with a low ratio of
surface area to volume and well constructed of
material which diminishes the daily extremes of
temperature. The roof should be well insulated.
In the Andes the adobe (dried mud) building has
the first meter or so of the walls made of stone, the
roof is of tile, grass or tin and walls are plastered with
mud to provide an airtight structure; the roof is
tightly fitted and the floor may be wood or dirt.
Because of the method of construction the diurnal
change is reduced (Baker 1966). In the Himalayas the
thermal protection of stone structures built for seminomadic occupation appears to be less. Sherpa
houses often have only one floor, with stone walls
and wooden roofs held on with stones. The ground
floor is without windows and provides quarters for
animals; the first floor is for human habitation.
Windows usually have no glass, but have wooden
shutters, and an open fire is placed in the center of
one side, but this provides only a transient increase in
temperature.
In north Bhutan houses are similarly constructed
but animals are kept in a yard. Cracks between stones
in both Bhutanese and Sherpa houses are filled with
earth. Tibetan houses maybe of more than one floor
and are often in terraces. Glass is rare and the houses
are heated by an open fire or stove. Nomads have
tents with a loose wide weave which enables warm air
to be entrapped but allows egress of smoke from
open fires and is waterproof. However, some seminomadic families have a stove with a chimney.

3.7

CLOTHING

Because of the generally low temperature and loss of

heat, particularly due to radiation and convection,
clothing with good insulation is necessary to provide
a warm microclimate. Trapped, still air is the best
insulation and wool is the best naturally available
insulating material; it resists compacting and loses
only 40 per cent of its insulating value when wet.
Garments that are loosely woven entrap more air
than those that are tightly woven.

A multiple layered system for garments is preferable to one thick layer because insulation can be
varied at will, thus minimizing perspiration. The
outer layer should be as impermeable to wind as
possible. A sheepskin coat is the best naturally available garment that has many of these characteristics,
and is usually worn with cotton or wool undergarments.
In general, Andean clothing conforms to the above
model and natural clothing is adequate for the
conditions encountered. Measurements of insulation
of normal clothing without hats, shawls and ponchos
showed values for men slightly less than those for
women (Little and Hanna 1978). The greatest
increase in surface temperature occurred in the
hands and feet. At night, Andean highlanders, who
use a bedding of skins, can maintain their metabolic
rate by light shivering that does not disturb sleep.
In the high Himalayan valleys and Tibet, clothing
assemblies are similar. The main garment is a thick
sheepskin 'chupa' with 15 cm (6 inch) sleeves which
when extended keep the hands warm; gloves are
never used. Normally the garment is gathered
around the waist by a belt and hitched up to the
knees so that there is a pocket for loose objects in
front of the chest. When the belt is loosened the
garment extends to the ground and thus can be
used as a sleeping robe; often in warm conditions
one or both shoulders are left bare. Under this is a
woolen shirt and often long woolen, cotton or
sheepskin trousers. Soft leather boots with decorative wool leggings extending to the knees are packed
with grass, straw or leaves but a Tibetan often may
walk in bare feet in the snow or through streams.
Some wear a felt hat or balaclava and, to prevent
snow blindness, yak hair is put in front of the eyes if
goggles are not available (Desideri 1712-27,
Moorcroft and Trebeck 1841, Vol. 1 p. 399) (Figure
3.3). Other methods used by Tibetans include
blackening the eyelids and wearing masks with tiny
eye holes, the rims of which are blackened
(MacDonald 1929, p. 182). Cotton clothing is
favored at high temperatures and low altitudes, but
nomads wear wool or sheepskin. Many now wear
wool sweaters and leather boots. Tibetan nomads
sleep resting on their elbows and knees with all
their clothes piled on their backs (Holditch 1907,
Duff 1999). This 'fetal position' diminishes surface
area and therefore heats loss: contact with the
ground is also minimal.

42 Geography and the human response to altitude

Figure 3.3 Yak hair 'goggles'.

Some Tibetan lamas have developed the ability to

'warm without fire'. The central core temperature is
kept raised under cold conditions, both by increasing
the metabolic rate, probably by continuous light
shivering, and also by the practice of g-tum-mo yoga,
which appears to involve peripheral vasodilatation
(Pugh 1963, Benson etal 1982).
Children have oil rubbed over their bodies and
adults seldom wash, the natural skin oils forming a
protective layer. Very few Tibetans living on the
plateau are obese (Bell 1928).

3,8

POPULATION

Most of the high altitude areas of the world are in the

economically least developed regions and for this
reason population numbers in relation to altitude are
difficult to obtain. Although the total population
living in mountainous regions is estimated at
400 million, the majority live at low altitude in the
valleys. De Jong (1968) 'guessed' that between 13 and
14 million people lived at altitudes above 3000 m. A
more accurate figure is 38 million (Hultgren 1997).
Worldwide, about 140 million people live over
2500m (WHO 1996).
In South America large populations have lived at
high altitude since prehistory and ,the Andean

population at the time of the Spanish conquest was

estimated as between 4.5 and 7.5 million. In 1980 it
was considered that between 10 and 17 million were
living at over 2500 m and in Peru 30-40 per cent of
the population of 4 million lived at or above this
height, with 1.5 per cent living at over 4000 m.
In Asia and Africa the estimates are less accurate.
On the Tibetan plateau, which consists of the
autonomous region of Tibet (Xizang) and Qinghai
province, the population is estimated as between 4
and 5 million. Lhasa (3658 m), in 1986, had about
130 000 inhabitants, mainly Tibetan, but recent
immigration of Han Chinese has increased this
number. Relatively small groups, nomads (at up to
5450 m) and miners (at up to 6000 m), live at higher
levels. Fairly large numbers live at altitudes exceeding
3000 m in the upper valleys of eastern Tibet, and in
Nepal about 60 000 live above this level, with a
number of villages in Dolpo being at 5000 m
(Snellgrove 1961). In Ethiopia about 50 per cent of
the total population of 26 million live above 2000 m.
Small populations in Mexico, the USA and the
former USSR live above 3000 m.
In the mainly subsistence economy of high
mountain regions, survival means the capacity to
perform physical work and high altitude natives
living at altitude have a capacity similar to that of low
altitude dwellers at low altitude. Many live to over
80 years of age; a Tibetan female hermit is said to
have died at the age of 130 years (Taring 1970)
(section 17.2.1), and the founder of traditional
Tibetan medicine, Yu-Thog, is considered to have
lived to the age of 125 years.
In tropical latitudes permanent settlements are
usually placed where both pasture and timber can be
used and the upper limit of habitation may fall
between the two. Further from the equator the upper
limit falls below the timber line and variation in
temperature becomes seasonal; the upper pasturelands are thus used for a semi-nomadic economy.
Permanently inhabited villages are found at lower
levels, with isolated groups of buildings or shelters on
the pastures occupied for the grazing season and
evacuated during the winter. Considerable migration
may occur and part of the population may always be
on the move. One mine, now closed, was worked at
5950 m in South America; although the miners lived
at rather lower altitudes, the caretakers lived there
permanently (West 1986a).
Those who spend periods at greater altitude are

Human response to cold and altitude 43

mountaineers, who have evolved specialized techniques of movement above the snow line. In winter,
movement across snow is essential for the feeding of
livestock quartered in isolated shelters. Since prehistoric times boards have been placed on the feet to
facilitate movement. The earliest references to
primitive skis are found in the Nordic sagas of 3000
BCE and, in northern Norway, rock engravings of
skiers are dated at around 2500 BCE. In the UK skis
were used in Cumberland at the start of the
eighteenth century. The modern sport dates from
1870. No historical evidence of the use of skis has
been found in South American or Tibetan
populations.
Highland populations, being strategically placed
between prosperous lowland centers, play a vital role
in trade. Because they are physiologically well
adapted they are capable of crossing high mountain
passes with heavy loads and use their animals to carry
produce. Major mountain passes have for centuries
been arteries for trade, the movement of people and
ideas, and the dissemination of disease. The closing
of passes such as the Nangpa La between the two
different economies of Tibet and Nepal caused a fall
in living standards until readjustments had been
made.

However, some studies have demonstrated different

physiological responses in high altitude residents to
experimental cold stress compared with low altitude
controls. These have been summarized by Little and
Hanna (1978) in drawing from work on Andean and
Tibetan high altitude residents.
In response to abrupt exposure to cold, high
altitude residents, when contrasted with sea level
Caucasian control subjects, show the following
responses:
no dramatic fall of core temperature
a slightly elevated basal metabolic rate
consistently high surface temperatures in
extremities
a slightly greater loss of body heat.
These changes are probably the result of lifelong
intermittent exposure to modest cold stress rather
than cold plus altitude. Pugh (1963) found a number
of these responses in a Nepalese pilgrim studied at
4500 m, who came from a village at only 1800 m.
Benson et al. (1982) found similar changes in
Tibetans practicing g-tum-mo yoga (an advanced
form of Tibetan yoga). The elevation of basal
metabolic rate may be the effect of hypoxia and cold
acting together (Little and Hanna 1978). Further
aspects of cold adaptation are considered in Chapter
24.

3.9 HUMAN RESPONSE TO COLD AND

ALTITUDE

3.9.2
The main environmental stresses of living in
mountain regions are cold and the hypoxia of
altitude.
3.9.1

Cold

Temperature is a more important factor than

altitude in colonizing high mountainous regions;
high altitude residents seem to withstand cold better
than sea level visitors to altitude.
Most of the process of adaptation to cold consists
of the adoption of clothing and housing which
reduce cold stress by maintaining a microclimate as
close as possible to the preferred temperature.

Hypoxia

In order to colonize the mountainous regions above

about 3000 m, acclimatization to the chronic
hypoxia of altitude is important. This response to
hypoxia is discussed in detail in Chapter 4. People
born and brought up at altitude have certain
advantages over lowlanders and this is discussed in
Chapters 4 and 17. However, long-term residence
also carries the risk of chronic mountain sickness
(Chapter 21). The question of whether altitude
populations have undergone adaptation in the biological sense of genetic selection for that environment is hotly debated. There is some evidence that
this has happened to a degree in the case of Tibetans
(see Chapter 17, section 17.5).

4
Altitude acclimatization
4.1
4.2

Physiological response to hypoxia

Acclimatization, deterioration and adaptation

44
45

SUMMARY
Altitude acclimatization is the physiological process
which takes place on going to altitude. It comprises a
number of responses by different systems in the
body, which mitigate the effects of the fall in oxygen
partial pressure so that the tissues of the body are
defended against this fall to a remarkable degree.
Probably the most important changes are the
increase in breathing (total ventilation) due to stimulation of the peripheral chemoreceptors (carotid
bodies) by hypoxia, and changes in the chemical control of breathing. Another is the well-known increase
in hemoglobin concentration in the blood. The time
courses of these responses vary but most of the
changes take place over a period of days up to a few
weeks. Individuals vary in the speed and extent to
which they can acclimatize. Apart from past history
of acclimatization there are no good predictors of
future performance.
Deterioration is a condition that is evident after
some time spent at extreme altitude. It comes on
over weeks above about 5500 m, and over days above
8000 m. It is characterized by loss of appetite, weight
loss, lethargy, fatigue, slowness of thought and poor
judgment.
Adaptation is a term used to describe the changes
that take place over generations by natural selection,
enabling animals and humans to function better at
altitude.

4.3
4.4

Oxygen transport system

Practical considerations and advice

46
48

4.1
PHYSIOLOGICAL RESPONSE TO
HYPOXIA
The response of the body to hypoxia depends crucially on the rate as well as the degree of hypoxia. For
instance, the effect on a pilot of sudden loss of oxygen supply in an unpressurized aircraft at the height
of the summit of Mount Everest is quite different
from the effect of similar altitude on a climber who
has spent some weeks at altitude. The pilot would
probably lose consciousness in a few minutes (Figure
4.1) whereas the climber, though very breathless, will
not only remain conscious but also be able to work
out his route and climb slowly upward.

Figure 4.1 The effect of sudden exposure to various altitudes. At

extreme altitude consciousness will be lost after an average time
indicated by the curve on the right. There is considerable variability
in this time. (Data from Sharp 1978.)

Acclimatization, deterioration and adaptation 45

The symptoms of acute hypoxia are few and subtle

(Figure 4.1). The effect of acute, often severe,
hypoxia has been studied intensively since Paul Bert
first pointed out the danger of ascent to high altitude
to early balloonists (Chapter 1). Figure 4.1 shows the
effect of sudden exposure to various increasing altitudes. At modest altitude breathlessness may be felt
on exertion and some rise in heart rate noticed but
the main effect is on the central nervous system. At
levels as low as 1500 m night vision is impaired
(Pretorius 1970). At 4000-5000 m some tingling of
the fingers and mouth may be noticed but, although
the subject would now definitely be hypoxic, there
would be very little subjective sensation to indicate
this fact. Above about 5000 m some subjects may
become unconscious and above 7000 m most will do
so (Sharp 1978). Figure 4.1 shows the average time to
loss of consciousness after sudden exposure to given
altitudes. It will be seen that, on acute exposure to the
altitude equivalent to the summit of Everest, the
unacclimatized subject remains conscious for only
about 2 min.
By contrast, the effect of hypoxia on an acclimatized person is much less. The main symptom is
shortness of breath on exertion. The preferred rate of
climbing amongst mountaineers is at about 50 per
cent V02max. This typically requires a ventilation of
about 50 L min'1 at sea level, whereas at 6300 m the
ventilation for this work rate will be about
160 L min"1, close to the maximum voluntary ventilation at sea level. The difference between the pilot
and the climber is due to a series of adaptive changes
in the body known as acclimatization. The changes
occur in various systems and with varying time
courses. These are illustrated in Figure 4.2, which
shows the futility of the frequently asked question,
'How long does it take to become acclimatized?'.
However, the most important changes are in the
cardiorespiratory system and the blood, with time
courses of days or a few weeks.
In some cases the changes of acclimatization
involve a biphasic response; for instance, the heart
rate response to hypoxia shows a rise within a few
minutes, followed by a fall over weeks at altitude
(Chapter 7). The .change measured can include two
responses with different time courses. For instance,
minute ventilation involves the rapid hypoxic ventilatory response within a few minutes, followed by
slow changes in both central and peripheral
chemoreceptor response over 1-20 days (Chapter 5).

Figure 4.2 Time courses of a number of acclimatization and

adaptive changes plotted on a log time scale, the curve of each
response denoting the rate of change, which is fast at first then
tailing off. Included are: heart rate, hyperventilation and
hypoventilation, the carbon dioxide ventilatory response (HCVR),
hemoglobin concentration ([Hb]), changes in capillary density
(Cap. Dens.), hypoxic ventilatory response (HVR) and the
pulmonary hypoxic pressor response (PHPR).

Similarly, the well-known increase in hemoglobin

concentration is due to a rapid decrease in plasma
volume, followed by a slow increase in red cell mass
(Chapter 8).

4.2 ACCLIMATIZATION,
AND ADAPTATION

4.2.1

DETERIORATION

Acclimatization

The term 'altitude acclimatization' refers to the

process whereby lowland humans and animals
respond to the reduced partial pressure of oxygen
(P02) in the inspired air. It usually refers only to the
changes in response to hypoxia seen as beneficial as
opposed to changes which result in illness such as
acute mountain sickness (AMS). Acclimatization is
then a series of physiological processes. Other

46 Altitude acclimatization

changes, resulting in illness, are pathological. The

processes of acclimatization all tend to reduce the fall
in PO2 as oxygen is transported through the body
from the outside air to the tissues.

4*2*2

Table 4.1 Maximum period spent at varying altitudes

without supplementary oxygen

5791
6760-731 5
7010
7467
7850
7925
8380
8450
8848

Deterioration

The term 'high altitude deterioration' was first used

by members of early Everest expeditions to denote
deterioration in mental and physical condition as a
result of prolonged stay at altitude. Filippi (1912,
p. 364) noted the condition during an expedition to
the Karakoram. He writes:
The atmosphere of the expedition did work some
evil effect revealing itself only gradually after several weeks of life above 17500 feet in a slow
decrease of appetite and consequent lack of nourishment without, however, any disturbance of
digestive function.

It is well known amongst climbers that staying at

extreme altitudes for long is deleterious. Altitudes
above 8000 m have been called 'the death zone' and
summit bids on peaks over this height are wisely
planned so as to spend as short a time as possible in
this zone (Table 4.1). Deterioration can frequently be
attributed to factors such as dehydration, starvation,
physical exhaustion and cold. However, in the
absence of such factors it seems that hypoxia per se
can cause deterioration if sufficiently severe (Pugh
1962a). The altitude at which this becomes manifest
is about 5000-6000 m, with considerable individual
variation. Highlanders can probably tolerate prolonged periods at a higher altitude better than can
most lowlanders (West 1986a).
High altitude deterioration (in the absence of
dehydration, starvation, etc.) is characterized by
weight loss, poor appetite, slow recovery from
fatigue, lethargy, irritability and an increasing lack of
willpower to start new tasks (Ward 1954).
The specific mechanisms underlying this deterioration are unknown. An attempt to investigate the
mechanism underlying the recovery from fatigue of
muscles under hypoxia was made by Milledge et al.
(1977), who followed the resynthesis of muscle
glycogen after depletion by exercise at sea level under
normoxia and hypoxia. They showed that, although
the rate of resynthesis was not significantly slowed by
hypoxia in the muscle overall, there was an

90-100
11
11
8
5
4
3
1
1

Source: Modified from Ward (1975, p. 238).

enhancement of the difference between the type I

and type II fibers. This suggested that hypoxia
depresses glycogen synthesis in type I though not
type II fibers. This might contribute to the slowness
of recovery from severe exercise at high altitude.
Over 5500 m malabsorption from the small gut (section 14.5) probably contributes to the weight loss as well
as a negative energy balance so deterioration accelerates.

4*23 Adaptation
People born and bred at altitude have certain characteristics which distinguish them from even well acclimatized lowlanders. There is debate about whether
these are due to environmental factors operating
during early growth, or genetic causes. The term
adaptation is used for characteristics thought to be
due to natural selection working on the gene pool.
Adaptation, in this sense, has certainly taken place in
animals such as the yak and llama. In the case of the
yak one example is the loss of the hypoxic pulmonary
pressor response which seems to be due to a single
dominant gene (Harris 1986). There is some evidence of a similar adaptation in Tibetans resident at
high altitude for generations, but this is, at present,
only suggestive (see section 17.5).

43
43.1

OXYGEN TRANSPORT SYSTEM

Introduction

Figure 4.3 shows the oxygen transport system at sea

level and at high altitude. This diagram can be used as

Oxygen transport system 47

10 mm Hg P0r This physical cause of P02 reduction is

beyond the control of the body and so applies equally
at altitude, though its effect is proportionately more
important there.
4.33

Image Not Available

Figure 4.3 The oxygen transport system from outside air through
the body at sea level and at an altitude of 5800 m. P& barometric
pressure; , rest; A, maximum work. (Reproduced with
permission from Pugh 1964.)

a 'table of contents' of changes due to acclimatization,

which will be followed in succeeding chapters. P02
falls at each stage as oxygen is transported from outside air: ambient P02 to inspired, to alveolar, to arterial, to mixed venous. The latter approximates to the
mean tissue P0r This forms a staircase or cascade of
P02. The process of acclimatization can be thought of
as reducing each step in this cascade as far as possible.
43.2

Ambient to inspired P02 (PI02)

The ambient P02 of dry air at sea level is about

160 mm Hg (20.9 per cent of 760 mm Hg, the barometric pressure). At an altitude of 5800 m in the
example shown in Figure 4.3 the barometric pressure
is just half that at sea level (Chapter 2), so the ambient P0z is also half the sea level value, 80 mm Hg. The
drop seen in the figure from ambient to inspired P02
of about 10 mmHg is due to the addition of water
vapor to the inspired air as it is wetted and warmed to
body temperature in the nose, mouth, larynx and
trachea. The water vapor pressure at body temperature is 47 mmHg, and this displaces almost

Inspired to alveolar P02 (PA02)

At sea level there is a drop of about 50 mm Hg at this

point in the oxygen transport system. This drop can
be thought of as being due to the addition of carbon
dioxide and the uptake of oxygen and so depends, in
part, on the metabolic rate. However, it also depends
on alveolar ventilation and for a given oxygen uptake
and carbon dioxide output the size of this reduction
is entirely due to ventilation. A doubling of ventilation results in a halving of this drop. If ventilation
were infinite there would be no reduction and alveolar gas would be fresh air. After acclimatization at
5800 m resting alveolar ventilation is approximately
doubled and this step in the system is halved, as
shown in Figure 4.3.
This increase in ventilation is one of the most
important aspects of acclimatization; the mechanisms underlying it, the changes in control of breathing, are dealt with in Chapter 5.
Figure 4.3 shows also the effect of exercise on the
oxygen transport system (the dashed lines). At sea
level the PA02 is little changed by exercise, but at altitude the increase of ventilation is far greater in
response to exercise than at sea level so that with
exercise the PA02 is increased and PACC,2 decreased
(Chapter 11).
43.4

Alveolar to arterial P02 (Pa02)

Oxygen passes across the alveolar-capillary membrane

by diffusion resulting in a small pressure drop but in
the normal lung this accounts for less than 1 mm Hg.
The total alveolar-arterial (A-a) P02 gradient at sea
level is about 6-10 mm Hg. The major part of this gradient is due to ventilation/perfusion ratio (V/Q)
inequalities. Even in the healthy lung the matching of
ventilation to blood flow is not perfect. In lung disease
such as emphysema or pulmonary embolism this mismatching results in much greater (A-a)PO2 gradients
and in significant hypoxemia. For a full discussion of
this important topic see West (1986b).
At altitude, at rest there is little change in the
(A-a)P02 gradient from its value at sea level. The V/Q

48 Altitude acclimatization

ratio inequality is modestly reduced, because of the

increase in pulmonary artery pressure due to hypoxia
(Chapter 7), reducing the gravitational effect on the
distribution of blood flow in the lung. However, this
is not enough to cause any measurable increase in the
diffusing capacity of the lung during acclimatization
(West 1962a).
On exercise at altitude, however, the (A-a)P02 gradient increases significantly and becomes important
in limiting exercise performance. This is shown as
the dashed line in Figure 4.3. This diffusion limitation, shown by West (1962), is explored more fully in
Chapters 6, 11 and 12.

43.5

(PvOj

Arterial to mixed venous P,02

The last drop in P02 shown in Figure 4.3 from arterial to mixed venous is due to the uptake of oxygen in
the systemic capillaries. Its magnitude is influenced
by the metabolic rate, the cardiac output and the
oxygen-carrying capacity of the blood, i.e. the hemoglobin concentration. The increase in hemoglobin
concentration is probably the best-known aspect of
acclimatization. A modest increase is beneficial in
that it increases the oxygen-carrying capacity of the
blood, and at altitudes up to about 4000 m this is sufficient to balance the reduction in oxygen saturation
due to reduced Pa0r However, the increase in viscosity of the increased hemoglobin concentration is the
price paid; if this is too great the cardiac output falls
and so oxygen delivery is reduced. There is also the
increased risk of vascular disorders. This aspect of
acclimatization is the subject of Chapter 8.
Changes in cardiac output with acute and chronic
hypoxia as well as other effects on the vascular system
are discussed in Chapter 7. Changes in the oxygen
dissociation curve at altitude, also important in this
section of the oxygen transport system, are reviewed
in Chapter 9.
Taking the body as a whole, the mixed venous P02
can be thought of as reflecting the mean tissue P0r It
can be seen (Figure 4.3) that the effect of these
processes of acclimatization is to maintain this critical P02 as near as possible to the sea level value.
Beyond this there is the possibility of adaptation at
the tissue level involving the microcirculation and
then intracellular mechanisms. These form the subject of Chapter 10.

4.4 PRACTICAL CONSIDERATIONS AND

ADVICE
A very real problem in the study of acclimatization is
that there is no single measure of the process.
Respiratory acclimatization is very important and
can be followed by measuring minute ventilation or
the alveolar or end-tidal -PCo2- The ventilation rises
with acclimatization and the PC02 falls exponentially
over the first few days at altitude. However, climbers
find that their performance continues to improve
over a longer period: presumably changes in other
systems underlie this further acclimatization. This
problem of how to measure the degree of acclimatization coupled with the very great individual variation in the rate and final degree of acclimatization
means that we still do not have answers to apparently
simple questions such as, 'Does exercise speed
acclimatization?'. There is also the problem that the
time of early and rapid acclimatization is also the risk
time for AMS. It is hard, and perhaps futile, to try to
separate the effect of any given strategy on preventing AMS and on speeding acclimatization since the
two are inextricably commingled. Thus the advice
given here is as much about preventing AMS as
about acclimatization. In the absence of hard data,
anecdotal evidence has to be relied on.

4.4.1

Rate of ascent

A rate of ascent which is slow enough to avoid AMS

should be chosen. This will inevitably be dictated, in
part, by the terrain, availability of camp sites, etc. A
rule of thumb often given is that above 3000 m each
night's camp should be about 300 m above the previous one and that every 2-3 days a rest day should be
added when the party remains based at the same site
for 2 nights. This is a rather slow ascent rate for many
individuals but will prove too fast for some. Where a
greater height gain has to be made, then a rest day
should be taken. During the 'rest' day trips to higher
altitude and back are considered beneficial by experienced climbers, probably because the greater altitude
and exercise stimulate acclimatization. However, it
should be noted that there is some evidence that
exercise is a risk factor for AMS (Roach et al. 2000).
See section 18.4.9 for a further discussion of exercise
and AMS.

Practical considerations and advice 49

4*4*2 Individual variability and

acclimatization
As already mentioned, there is great individual variation in the rate and degree of acclimatization. Some
may acclimatize rapidly to moderate altitude but
then find that they simply cannot tolerate an altitude
above, say, 7000 m. Others may take time to acclimatize but then go well to extreme altitude. Usually, as
with susceptibility to AMS, past experience is a good
guide to future performance but apart from this
there are no reliable predictors for good acclimatization.

4*43

Age, gender and experience

There are very few data to answer the frequently

asked question about the effects of age or gender on
acclimatization. If anything, older people are less
susceptible to AMS than young people and seem to
acclimatize just as well. There does not seem to be
any important difference between men and women
in this respect. There is a strong impression that
experienced mountaineers acclimatize better than
novices. (See Chapter 28 for further discussion of
acclimatization in women, children and elderly
people.)

4*4*4 Pre-acclimatization and carryover acclimatization

There is increasing interest in methods by which
people can achieve some degree of acclimatization
before going to the mountains. Methods suggested
include intermittent exposure to simulated altitude in
chambers or by breathing low oxygen mixtures. There
is no doubt that living in a chamber for a number of
days at simulated altitude will achieve acclimatization.
There is an impression that the degree of acclimatization is not as great as that achieved in the mountains,
perhaps because of the lack of exercise. West (1998,
pp. 358-63) argues the case for this being true for the

long-term studies of Operation Everest I and II.

However, incarceration in a chamber for days is not
practicable or acceptable for most climbers.
Intermittent exposure such as spending a few hours a
day in a chamber, usually with exercise, i.e. training
under hypoxia, or sleeping in a hypoxic environment
has been suggested. At present there are no studies to
show that these measures do produce beneficial effects.
Savourey et al. (1998) studied the effect of 8 h daily for
5 days at 4500 m equivalent altitude on various hormones and biochemical measures but found very little effect with this dose of pre-acclimatization. Garcia
et al. (1999) had their subjects breath 13 per cent oxygen (equivalent to 3800 m) for 2 h daily for 12 days.
They found the hypoxic ventilatery response increased
significantly, reaching a peak at 5 days but there was
no change in ventilation, PC02 or arterial oxygen saturation (Sa02). They found a reticulocytosis but no
change in hemoglobin concentration or hematocrit. It
seems that intermittent hypoxia has a qualitatively different effect than does chronic hypoxia. So one can
only say that pre-acclimatization may well confer some
benefit, but an extra few days at altitude would probably be as good and more pleasant.
If pre-acclimatization is attempted, how quickly
should a climber get out to the mountains? In other
words, how long does acclimatization last? There are
very few hard data to guide us, though one study by
Lyons et al. (1995) showed that a group of subjects
who had been at 4300 m for 3 weeks retained some
beneficial effect after 8 days at low altitude compared
with a group who had had no altitude exposure. A
later study by the same group (Beidleman et al. 1997)
with a similar protocol helped to quantify this carryover effect. After 8 days at sea level they calculated
that on average the retained effect on Sa02 was 92 per
cent, on plasma volume it was 74 per cent and on the
lactate concentration at 75 per cent V02max it was 58
per cent. These figures support anecdotal experience.
The effect of acclimatization probably falls off exponentially with time over perhaps 2-3 weeks, though
some feel there is some residual benefit even after
months at sea level.

5
Ventilatory response to hypoxia and
carbon dioxide
5.1

Introduction

5.2

Hypoxic ventilatory response (HVR)

5.3
5.4

Carotid body
HVR at sea level

51
51
52
53

5.11 Acute normoxia in acclimatized subjects

5.12 Carbon dioxide ventilatory response and
acclimatization
5.13 Mechanism for resetting HCVR

5.5

HVR at high altitude

53

5.14 Mechanisms for reduction in CSF bicarbonate

5.6
5.7

HVR and acute mountain sickness

HVR and altitude performance

55
56

5.15 Brain acid-base balance

62

5.8

HVR and sleep

5.9

HVR at altitude: conclusions

57
57

5.16 Dynamic carbon dioxide response

5.17 Longer term acclimatization

63
64

5.10 Alveolar gases and acclimatization

57

SUMMARY
Of all the changes that take place in the physiology of
a person acclimatizing to altitude, those resulting in
an increase in ventilation are probably the most
important. There are changes in both the hypoxic
ventilatory response (HVR) and the hypercapnic
ventilatory responses (HCVR). The changes in HVR
are more difficult to measure and there is still some
debate about the details, but the consensus view is
now that HVR increases with time at altitude over a
period of days to a few weeks. The changes in HCVR
were characterized 40 years ago and include a shift to
the left and a steepening of the carbon dioxide
response line. That is, a person when acclimatized
responds to a lower Pcc,2 and is more sensitive to
carbon dioxide than when unacclimatized. The time
course of these changes is exponential, with almost
half taking place in the first 24 h and most of the
change being complete in about 2 weeks. These

concentration

58
58
59
60

changes in the chemical control of breathing underlie the well-known increase in ventilation and result
in a lower PC02 and higher P02 characteristic of
acclimatization. The mechanism underlying the
increased carbon dioxide sensitivity is probably the
documented reduction in bicarbonate concentration
in cerebrospinal fluid (CSF) and presumably brain
extracellular fluid (ECF).
High altitude residents have similar HCVR but
generally have blunted HVR compared to acclimatized lowlanders. HVR does not predict susceptibility to acute mountain sickness (AMS), though
subjects susceptible to high altitude pulmonary
edema (HAPE) do have low HVR. Some studies
have found a correlation between HVR and
performance at extreme altitude but some elite
climbers have HVR in the normal range, and high
altitude residents (Sherpas and Andean peoples)
who tend to have low HVR perform very well at
extreme altitude.

Hypoxic ventilatory response (HVR) 51

5.1

INTRODUCTION

The increase in ventilation that takes place in the

first few days at altitude is one of the most important aspects of the acclimatization process. It
results in higher alveolar and arterial P0z and lower
PC02 levels than would have obtained if the ventilation were unchanged. The cause of this increased
ventilation is a change in the chemical control of
breathing. Interest in the mechanisms underlying
these changes goes back to the early years of the
twentieth century. Haldane, who had shown that
the level of carbon dioxide in the body was stable,
soon realized that altitude resulted in depression of
PCo2 due to increased ventilation. He suggested
that his colleague Mabel FitzGerald measure the
alveolar PC02 in residents at mining camps at
various altitudes in Colorado. She found that the
PC02 fell linearly with altitude (FitzGerald 1913).
Since then physiologists have continued to investigate these mechanisms and their work is reviewed
in this chapter.
There are two sensing systems for the chemical
control of breathing: the peripheral chemoreceptors
(the carotid and aortic bodies), and central chemoreceptors situated in the medulla. There are three
chemical drives to ventilation: hypoxia, pH and
carbon dioxide. The peripheral chemoreceptors
principally sense hypoxia, though they also respond
to carbon dioxide and pH, whereas the central
chemoreceptors sense changes in pH, which are
frequently due to changes in PCo2-

from individual to individual and does not usually

begin until the inspired P02 is reduced to approximately 100 mmHg (equivalent to about 3000 m
altitude) (Rahn and Otis 1949). This corresponds to
an alveolar P02 of about 50 mm Hg. Thereafter, as
inspired P0z is further reduced ventilation increases
more rapidly.
The relationship of ventilation to P02 is hyperbolic, as shown in Figure 5.1. However, if arterial
saturation is measured by an oximeter the relationship between it and ventilation is found to be
approximately linear (Figure 5.1). The Pa02 at which
ventilation starts to increase corresponds to the P02
at which the oxygen dissociation curve begins to
steepen.
The actual effect of acute hypoxia on ventilation
will depend upon whether PC02 is allowed to fall or
not. Unless the experimental arrangement allows
control of PACC,2, a rise in ventilation will result in a
fall of PC02. As PC02 is reduced some drive to breathing will be lost so that the full hypoxic response is not
seen.

5.2 HYPOXIC VENTILATORY RESPONSE

(HVR)
The HVR is the increase in ventilation brought about
by acute hypoxia. This is not a simple linear response
and is complicated by the effect of ventilation on
PCo2- As ventilation rises in response to hypoxia, Pcc,2
falls. Thus the carbon dioxide drive to breathing is
reduced and the hypoxic response is masked unless
measures are taken to prevent this fall in PCo2If the inspired P02 is reduced acutely, i.e. over a
period of a few minutes, either by breathing a low
oxygen mixture or by decompression in a hypobaric
chamber, the minute ventilation is increased.
However, this increase in ventilation varies greatly

Figure 5.1 Hypoxic ventilatory response to PA02 and arterial

oxygen saturation fSa02J.

52 Ventilatory response to hypoxia and carbon dioxide

53

CAROTID BODY

Before considering HVR further, the transduction of

the hypoxic response will be briefly considered. A
transducer effects the conversion of one mode of
signal to another, in this case from Pa02 to a neural
signal by the carotid body.

53.1

Historical

The stimulating effect of oxygen lack on respiration

had been known for many years before it became
apparent at the turn of the century that, under
normal sea level conditions, carbon dioxide was the
main chemical stimulus to ventilation.
In the late 1920s, the father and son team of
Heymans and Heymans in Belgium, using complex
cross-circulation experiments in dogs, localized the
main sensing organ for hypoxia to the carotid body
(Heymans and Heymans 1927). Not long afterwards
Comroe (1938) showed that the aortic bodies have a
similar function. These bodies are known collectively
as the peripheral chemoreceptors. However, in most
animals, including humans, the main organ for
transduction of the hypoxic signal is the carotid body
and if this is removed or denervated, acute hypoxia
actually causes depression of ventilation.

53.2
Anatomy and physiology of the
carotid body
The human carotid body weighs about 10 mg and is
situated just above the bifurcation of the common
carotid artery. It has an extremely rich blood flow for
its mass and oxygen consumption, and thus it is a
very low extraction organ (i.e. it extracts only a very
small percentage of the oxygen in the blood
presented to it). This explains how it is able to
respond to arterial P02 (or saturation) and not to
oxygen content. Thus it responds to hypoxemia but
not anemia or reduced flow. This is appropriate since
an increase in ventilation would not help the
organism overcome the tissue hypoxia caused by
anemia or low cardiac output, but does help in a
hypoxic environment.
Although an enormous amount of research work
has been carried out on the carotid body, it is still
not clear which cells or nerves actually sense the

hypoxemia nor which transmitters are involved. It has

been assumed that the glomus cells (type I), the characteristic cells of the carotid body, are the sites of
chemoreception and that modulation of neurotransmitter release from the glomus cells by physiological and chemical stimuli affects the discharge rate
of the carotid body afferent fibers. Undoubtedly the
signal is modified, enhanced or suppressed by parts of
the system not involved with the primary sensing
process.
Two key observations need to be explained:
Carotid body chemoreceptors are excited
physiologically by hypoxia, hypercapnia and
acidosis.
Chemical agents which interfere with
mitochondrial oxidative phosphorylation (and
therefore reduce the ATP/ADP ratio) stimulate
chemoreceptors.
There are two leading hypotheses:
Hypoxia may slow down mitochondrial electron
transport owing to the presence of a reduced
affinity cytochrome in the oxygen transport
chain. This could stimulate neurotransmitter
release from glomus cells by progressive
breakdown of the mitochondrial electrochemical
gradient and release of mitochondrial calcium
into the cytoplasm. The elevated intracellular
calcium would then cause release of the
neurotransmitter. Metabolic blockers which
interfere with electron transport and oxidative
phosphorylation would have a similar effect
(Mulligan et al. 1981, Biscoe and Duchen
1990).
Glomus cells may have potassium channels in
their cell membranes that are modulated by the
partial pressure of oxygen. The probability that
the channel is open decreases with hypoxia and
acidosis and the result is a reduction in overall
potassium conductance which causes membrane
depolarization. This could explain
chemotransduction as follows: the membrane
depolarizes, voltage sensitive calcium channels
open, and these allow extracellular calcium to
enter the cell. The elevated intracellular calcium
then promotes neurotransmitter release.
The potassium channel has been demonstrated in
submicron-sized membrane patches which continue
to be modulated by oxygen when removed from the

HVR at high altitude 53

cell. It has been suggested that the channel itself contains a heme group which may interact with oxygen
directly, thus modifying channel confirmation and
the probability of its being open (Ganfornina and
Lopez-Barneo 1991), but the heme group has not
been identified (Lahiri and Delaney 1975).
The glossopharyngeal nerve carries sensory fibers
from the carotid to the central nervous system (CNS)
where the sensory input stimulates the respiratory
center or centers in the pons. Another area of uncertainty is the existence or otherwise of efferent
fibers in the glossopharyngeal nerve going to the
carotid and modifying its response and the
suggestion that sensory nerves and synapses can
work both ways, i.e. as afferent or efferent.
Dopamine is the most abundant transmitter
found in the carotid body, followed by norepinephrine (noradrenaline) and 5-hydroxytryptamine.
There are also small quantities of acetylcholine and
enkephalin-like peptides in some glomus cells.
Hypoxia increases the rate of release of dopamine
from glomus cells.
It should be noted that although the most important function of the peripheral chemoreceptors
(carotid and aortic bodies) is to respond to hypoxia,
they do also respond to any increase in Pac02 and
decrease in arterial pH. However, the greatest
response to PC02 is via the central chemoreceptors in
the brain stem (see section 5.13.1).

5.4

5.4.1

HVR AT SEA LEVEL

Methods for measuring HVR

A number of different methods have been used to

measure HVR, each having its advantages and disadvantages. Probably the most popular method for
studies involving large numbers of subjects is the
rebreathing method using an oximeter to measure
oxygen saturation continuously while the PC02 is
held constant (Rebuck and Campbell 1974). More
recently, Robbins and his group in Oxford have
used a series of square wave pulses of hypoxia keeping the carbon dioxide constant and then fitting a
single compartment model which yields a
parameter Gp, the hypoxic sensitivity (Ren and
Robbins 1999).

5.4.2

Variability of HVR

The range of HVR found in healthy sea level

residents is wide. The coefficient of variation varies
between 23 and 72 per cent in different studies
(Cunningham et al. 1964, Weil et al. 1970, Rebuck
and Campbell 1974).
Various groups of subjects at sea level have been
shown to have lower HVRs than controls, for
instance endurance athletes (Byrne-Quinn et al.
1971) and swimmers (Bjurstrom and Schoene 1986).
With increasing age HVR becomes lower
(Kronenberg and Drage 1973, Chapman and
Cherniak 1986, Poulin et al. 1993) and respiratory
depressant drugs and anesthetics inhibit HVR (Sahn
etal 1974, Davis etal. 1982).

5.5

5.5.1

HVR AT HIGH ALTITUDE

HVR and acclimatization

During the first few days at altitude, respiratory

acclimatization takes place. This is shown by an
increase in ventilation and a decrease in PAC02. PA02
falls immediately on exposure to acute altitude and
then rises (as PACo2 falls) over the next few days. The
rise in ventilation on acute exposure to hypoxia is
mediated by the HVR (by definition) but further
increase in ventilation is due to changes in the ventilatory response to carbon dioxide (see section 5.12)
and also in the sensitivity of the carotid body with
more time at altitude.
The peripheral chemoreceptors are essential for
normal respiratory acclimatization, and animals
which have had their carotid bodies denervated fail
to acclimatize normally (Forster et al. 1981, Lahiri et
al 1981, Smith et al 1986). After denervation these
animals have raised Pacc,2, which rises further with
acute hypoxia. With chronic hypoxia, at least in
some cases, there is a small fall in Pac02 which has
been taken by some workers as evidence of acclimatization (Sorensen and Mines 1970). This and other
evidence suggests that chronic hypoxia produces
some effect on ventilation via mechanisms other
than the carotid body, possibly via cerebral
metabolism. All agree, however, that denervated
animals appeared ill at altitude and a number died.

54 Ventilatory response to hypoxia and carbon dioxide

It might be expected that exposure to hypoxia of

some days or months would result in attenuation or
sensitization of the HVR. Michel and Milledge
(1963) found an increase in the hypoxic parameter A
in three out of four subjects after 1-3 months at
5800 m. Parameter A is the 'shape' parameter of the
hyperbola relating PA02 to ventilation (Figure 5.2).
The larger the value the greater the response. There
was no change in the other hypoxic parameter, C
(the P02 at which theoretically ventilation becomes
infinite, the P02 asymptote of the hyperbola). Cruz et
al. (1980) also found an increase in parameter A after

Figure 5.2 Two steady-state inhalation experiments typical of a

lowlander (upper panel) and a Sherpa Highlander (lower panel).
The numbers refer to the P02 of each point. There is no significant
difference in HCVR but the 'closed fan' of the Sherpa indicates very
little HVR. Letters A-D refer to the parameters relating HVR (A and
C) and HCVR (B and D). (From Milledge and Lahiri 1967.)

74 h of altitude exposure; this was not seen in

subjects whose PACC,2 was not allowed to fall.
The question of a change in chemoreceptor
responsiveness during acclimatization has been
reviewed by Weil (1986), who points out that a
number of studies have not found any change in
HVR with acclimatization, although the presence of
hypocapnic alkalosis, which has a depressant effect
on HVR at sea level, may have obscured a real
change. However, more recent studies have found an
increase in responsiveness. Barnard et al. (1987)
found neurophysiological evidence of increased
sensitivity of the carotid body for hypoxia in cats
after chronic hypoxia of 28 days but not after only
2-3 h. Vizek et al. (1987) also presented evidence
from work in cats of an increase in HVR (parameter
A) after 48 h hypoxia. Engwall and Bisgard (1990)
found an increase in HVR after 4 h of hypoxia in
awake goats. Yamaguchi et al. (1991), Sato et al.
(1992, 1994) and Goldberg et al. (1992) found a
significant increase in HVR in lowland subjects after
acclimatization at 3730-4860 m compared with preexposure values. Masuda et al. (1992) measured
HVR serially in seven lowland subjects after arrival at
Lhasa (3658 m) as they acclimatized over 27 days.
They found a biphasic response, i.e. a small decrease
over the first 3-5 days then a considerable increase
from day 5 to 27.
Robbins's group in Oxford have carried out a
series of chamber studies in which the inspired gases
can be controlled so as to keep the subject's end-tidal
PC02 constant. Thus they are able to study the
changes in HVR with hypoxia over first 8 h and later
48 h with or without the confounding effect of
respiratory alkalosis mentioned above. They found
that HVR did increase under isocapnia (Howard and
Robbins 1995). They also showed that acclimatization had taken place even with isocapnia in that
ventilation was raised under acute hyperoxia
(Tansley etal 1998). Using a 48 h chamber exposure,
under either isocapnic or poikilocapnic hypoxia, the
increase in hypoxic sensitivity started within 12 h
and reached peak at about 36 h. That there was no
difference between isocapnic and poikilocapnic
results suggests that the respiratory alkalosis, normal
in early acclimatization, is not an important part of
the mechanism for this process, though it is for the
changes in carbon dioxide sensitivity.
This increase in HVR over the period of a few days
to a few weeks could explain the further increase in

HVR and acute mountain sickness 55

ventilation over this period of altitude exposure. The

question of the role of HVR in effecting the change in
carbon dioxide response and brain extracellular
bicarbonate concentration is considered in section
5.13.
In humans, after decades at altitude, HVR becomes
blunted (section 5.5.2). In cats this blunting is seen
after 3-5 weeks if the hypoxia is sufficiently severe.
Tatsumi et al. (1991) showed blunting of HVR after
this time at a simulated altitude of 5500 m. They also
found that HVR, measured by recording from the
carotid sinus nerve, was blunted. They considered
that both central and peripheral parts of the system
contributed to the reduction in overall HVR.

5.5.2

Weil et al. (1971) showed blunting of HVR in

white people born and living at Leadville, Colorado
(3100 m), HVR being only 10 per cent of that found
in the sea level controls.

5.53
Lowlanders resident at high
altitude
Early studies of lowland subjects resident for a few
years at high altitude suggested that HVR remained
unchanged indefinitely (Sorensen and Severinghaus
1968, Lahiri et al. 1969). However, in a study of
lowlanders resident at altitude for decades (Weil et
al. 1971) it was shown that blunting did take place
slowly.

HVR and altitude residents

5.5.4

Chiodi (1957) reported that altitude residents in the

Andes had higher PACC,2 than acclimatized lowlanders. Severinghaus et al. (1966a) showed that
Andean Indians born and living at altitude had a
blunted HVR and similar findings were reported in
Sherpas, natives to high altitude in the Himalayas
(Lahiri and Milledge 1967, Milledge and Lahiri
1967). Steady-state inhalation experiments typical of
a lowlander and a Sherpa are shown in Figure 5.2.
The 'opened-out fan' of the lowlander indicates a
brisk HVR whereas the 'closed fan' of the Sherpa
shows that changing PA02 between 200 and
30 mm Hg has very little effect on ventilation. These
early reports have been confirmed and Lahiri (1977)
has reviewed the data from these studies. There is
considerable variability amongst these people, the
HVR varying from almost zero response to values
within the lowlander range. One study (Hackett et al.
1980) claimed that Sherpas did not show this blunted
HVR. However, even this study showed that HVR
was lower in Sherpas with the longest altitude
exposure. More recently Zhuang et al. (1993) found
HVR in Tibetan subjects at 3658 m to be lower than
in acclimatized Han Chinese at the same altitude.
Recently there has been interest in comparing
Tibetan with Andean high altitude residents. Beall et
al. (1997a) studied 320 Tibetans and 552 Andean
subjects. They found resting ventilation to be higher
in Tibetans by a factor of about 1.5, and their HVR to
be roughly double that of the Andean subjects.
Comparison of these two populations is discussed
further in Chapter 17.

Highlanders resident at sea level

The HVR was found not to change in high altitude

natives who came down to live at low altitude (Lahiri
et al. 1969), although Vargas et al. (1998), also from
South America, found no difference in HVR between
high and low altitude natives measured at low
altitude, the high altitude natives having been at low
altitude for only a few years.

5.5.5

The development of blunted HVR

Lahiri et al. (1976) found evidence in Andean

Indians that HVR was normal in children and
became blunted only as they grew into adulthood at
altitude. They suggested the rate of blunting was
more rapid the higher the place of residence. Weil et
al. (1971) showed that in white subjects blunted
HVR also developed only after decades of high
altitude residence. In cats blunting can be induced in
3-4 weeks if the altitude is as high as 5500 m but not
below 5000 m (Tatsumi etal. 1991).
These findings prove that the blunting of the HVR
takes many years to develop in humans and is due to
environmental and not genetic factors.

5.6 HVR AND ACUTE MOUNTAIN

SICKNESS
AMS is a condition affecting otherwise fit people on
ascending rapidly to altitude. For details of

56 Ventilatory response to hypoxia and carbon dioxide

symptomatology, etiology and treatment, see Chapter

18. It would seem axiomatic that a brisk HVR by
increasing ventilation reduces the degree of hypoxia
and must be protective against AMS. There is some
evidence that this may be the case, but it is by no
means overwhelming.
Hu etal. (1982) showed that six good acclimatizers
had brisk HVR whereas four poor acclimatizers had
blunted responses. Richalet et al. (1988) found that in
128 climbers going to altitude on various expeditions
a measure of HVR carried out before departure indicated that a low response was a risk factor for AMS.
However, high altitude residents and peoples native
to high altitude have blunted HVR (see section 5.5.2)
and yet tend to be less subject to AMS than lowlanders. In lowland climbers of varying altitude
experience, Milledge et al. (1988, 1991a) found no
correlation between HVR measured before
expeditions to Everest, Mount Kenya and Bolivia and
the symptom score for AMS, in the first few days after
arrival at altitude.
Masuda et al. (1992) found an initial decrease in
HVR 1-5 days after arrival at Lhasa (3700 m) followed
by an increase and suggested that this might explain
why these first few days are the time of risk for AMS.
These studies all considered a correlation, or lack
of it, between HVR and simple or benign AMS.
Hackett et al. (1988b) studied seven male patients
with HAPE and found HVR was low, especially in
those with most severe hypoxemia. More recently
Hohenhaus et al. (1995) measured HVR in 30
subjects proved to be HAPE susceptible compared
with a control group. They concluded that a low
HVR is associated with an increased risk of HAPE
but not with simple AMS.

Climbers with a brisk HVR were found to suffer

greater impairment of mental performance at
altitude (Hornbein et al. 1989), presumably as a
result of reduced brain blood flow due to lower Pzco2
(see Chapter 16 for details of this work).
Schoene (1982) showed that 14 high altitude
climbers had significantly higher HVR than 10
controls. During the 1981 American Medical
Research Expedition to Everest, Schoene etal. (1984)
extended this work, showing again that the HVR
measured before and on the expedition correlated
well with performance high on the mountain (Figure
5.3). They also showed that, at altitude, the fall in
oxygen saturation on exercise is greater in subjects
with a low HVR and least in those with a brisk
response. Thus, subjects with a blunt HVR are not
only more hypoxic at rest but have even greater
hypoxia on exercise than brisk responders. This is
because there is a correlation between HVR and
exercise ventilatory response (Martin et al. 1978).
Matsuyama et al. (1986) found that five climbers
who reached an altitude of 8000 m on
Kangchenjunga (8486 m) had a higher HVR than
five climbers who did not.

5.7 HVR AND ALTITUDE

PERFORMANCE
Apart from AMS, some people 'go well' at altitude
whereas others, just as athletically fit, seem much
more adversely affected. In general, there is a good
correlation between freedom from AMS and good
altitude performance. Again, it would seem advantageous for a mountaineer to have a brisk HVR in
order to maintain a better oxygen supply to the
working muscles. However, the evidence for this is
conflicting.

Figure 5.3 HVR and height reached on Mount Everest by eight

mountaineers on the American Medical Research Expedition to
Everest 1981. (Redrawn from data of Schoene et al. 1984.)

Alveolar gases and acclimatization 57

However, the blunted HVR in peoples native to

high altitude who perform at least as well as lowlanders argues against the necessity for a brisk HVR.
They have probably adapted in other ways at a tissue
level (Chapter 10). There is also evidence of not so
brisk HVR in top level climbers. On the British
Mount Kongur Expedition four elite climbers were
found to have less HVR than four scientists on the
same expedition (Milledge et al. 1983c). Schoene et
al. (1987) studied one of the two climbers to first
reach the summit of Mount Everest without supplementary oxygen and found him to have a low HVR.
Oelz et al (1986) also showed that six elite climbers
who had all reached at least 8400 m without supplementary oxygen had HVRs no different from controls. In a prospective study of 128 climbers going on
expeditions to the great ranges, Richalet et al. (1988)
found that a measure of HVR did not correlate with
the height reached, whereas maximal oxygen consumption (V"02 max) measured at sea level did.
Serebrovskaya and Ivashkevich (1992) found that
subjects with the highest HVR had higher physical
capacity at moderate altitude but tolerated extreme
hypoxia less well, in that the P02 at which they had a
disturbance of consciousness was higher than
subjects with less brisk HVR.

5.8

HVR AND SLEEP

A feature of sleep at high altitude is periodic breathing. This not only disturbs sleep, the subject often
waking with a distressing sensation of suffocation,
but also results in quite profound hypoxia for short
but repeated periods following the apneic phase of
the periodic breathing (see Chapter 13). It may be
that these short but repeated periods of profound
hypoxia are more detrimental than a steady
moderate hypoxia, although the peak and average
Sa0z tend to be higher during periodic breathing.
Lahiri et al. (1984) have shown that to produce
periodic breathing a brisk HVR is needed, so in this
respect a brisk HVR may be a disadvantage.

5.9

HVR AT ALTITUDE: CONCLUSIONS

Animals that have had their carotid bodies

denervated appear sick on being taken to altitude

and have a high mortality, so an HVR sufficient to

at least counter the central depressant effect of
hypoxia is clearly beneficial. Whether a very brisk
HVR is more advantageous than a more modest
response is questionable on available evidence.
Relative hypoventilation at altitude is probably a
risk factor for AMS but the HVR measured at sea
level is only one factor in determining the ventilation after a day or two at altitude. The speed of
respiratory acclimatization may be more important
than the HVR.
In subjects with a brisk HVR it seems likely that
periodic breathing will begin at lower altitudes and
be present for more of the night than in subjects with
a more blunted HVR. Mental performance at
altitude and even after return to sea level may be
more impaired in subjects with a brisk HVR (see
Chapter 16).
Lowlanders with little or no altitude experience
may possibly acclimatize faster and be freer of AMS if
they are endowed with a brisk HVR. Highlanders
with decades of altitude living probably develop
adaptations at the tissue level which allow them to
dispense with this 'emergency' response to hypoxia
and avoid the need for hyperventilation.
Highly experienced climbers may also have made
some progress towards this adaptation and so may
not require a brisk HVR to avoid mountain sickness
and perform well at altitude.

5.10
ALVEOLAR GASES AND
ACCLIMATIZATION
It has been pointed out that if PI02 is progressively
reduced over a few minutes there is very little effect
on ventilation until PI02 has fallen to about
100 mm Hg (equivalent to about 3000 m). However,
in residents at altitudes lower than this, ventilation is
increased. This effect of chronic hypoxia in increasing ventilation (over and above that due to acute
hypoxia) is an important aspect of respiratory
acclimatization.
Minute ventilation at rest is not easy to measure
accurately because the placing of a mouthpiece or a
mask on a subject itself tends to increase ventilation.
Therefore it is usual to use PAC02 as an index of
ventilation since during steady state there is a close
(inverse) relationship between PACC,2 and ventilation.

58 Ventilatory response to hypoxia and carbon dioxide

a gas mixture appropriately enriched with oxygen.

The ventilation is reduced and the PAC02 rises but
does not return to sea level values. The remaining
elevation of ventilation and depression of PAC02 indicate the degree of respiratory acclimatization. This is
most accurately measured when ventilation is
recorded during exercise.
Figure 5.5 shows results from two typical experiments (Milledge 1968). It will be seen that by breathing sea level PI02 the increase in ventilation at altitude
compared with sea level is reduced by about 40 per
cent at any given submaximal work rate.
Figure 5.4 Alveolar gas concentrations and altitude. The upper
line represents the ?02 and PC02 found in subjects actually exposed
to increasing hypoxia in a chamber. The lower line is from
residents at various altitudes and from acclimatized
mountaineers. (After Rahn and Otis 1949.)

The classical description of the effect of altitude on

alveolar gases is by Rahn and Otis (1949) on the
oxygen/carbon dioxide diagram (Figure 5.4).
Alveolar gases in subjects acutely exposed to varying
PI02 in a decompression chamber are compared with
results from residents at various altitudes culled from
the literature.
It will be seen that in chronic hypoxia PC02 falls in
a linear fashion from sea level up to altitudes of about
5400 m, above which Pcc,2 falls more rapidly so that
the line dips down. These are altitudes above the
highest permanent habitation and are from climbers
who have been there for some days or weeks. At this
altitude complete acclimatization is probably not
possible; the physiology is further discussed in
Chapter 12.
Figure 5.4 also shows that at about 5000 m the
difference in alveolar gases between the two lines, i.e.
acclimatized and unacclimatized subjects, is greatest.
The PACC,2 is 10-12 mmHg lower in acclimatized
subjects, indicating an increase in ventilation of over
40 per cent compared with unacclimatized subjects.

5.11
ACUTE NORMOXIA IN
ACCLIMATIZED SUBJECTS
Respiratory acclimatization can be demonstrated by
returning acclimatized subjects to normal (sea level)
P02 either by rapid return to sea level or by breathing

Figure 5.5 Effect of breathing sea level PI02 on exercise minute

ventilation in two acclimatized subjects (O) compared with their
ventilation during air breathing at altitude (A) and at sea level
(x). (Milledge 1968.)

5.12
CARBON DIOXIDE VENTILATORY
RESPONSE AND ACCLIMATIZATION
An important aspect of respiratory acclimatization is
the change in carbon dioxide ventilatory response
(HCVR) measured either by the steady state (Lloyd
etal 1958) or by a rebreathing method (Reed 1967).
The effect of time at altitude on the HCVR is
shown in Figure 5.6, which is from the work of
Kellogg (1963). The steady-state method was used in
three subjects to measure the HCVR before ascent to
White Mountain. The measurement was repeated a
few hours after arrival by road at 4350 m and thereafter at intervals as indicated on the figure. It will be
seen that the HCVR line shifts progressively leftwards and steepens. Voluntary hyperventilation of
only 6 h duration breathing air has a significant effect
in shifting the carbon dioxide response curve to the
left (Ren and Robbins 1999).

Mechanism for resetting HCVR 59

Image Not Available

Figure 5.6 Effect of acclimatization on HCVR
at an altitude of 4340 m. V, ventilation.
(Reproduced with permission from Kellogg
1963.)

5.13
5.13*1

MECHANISM FOR RESETTING HCVR

Central chemoreceptors

Although the peripheral chemoreceptors are

sensitive to changes in Pcc,2 and hydrogen ion
concentration, the main sensor for changes in PC02 is
the central medullary chemoreceptor. This is a
paired region of the CNS situated just beneath the
surface of the fourth ventricle in the medulla. Work
by Mitchell (1963) has shown that this area is
sensitive to changes in hydrogen ion concentration
in the brain ECF. Such changes are brought about
primarily by changes in arterial Pcc,2The blood-brain barrier is readily permeable to
dissolved carbon dioxide, less permeable to
hydrogen ions and even less to bicarbonate. Thus, a
rise in Pacc,2 is rapidly reflected in CSF Pcc,2 and
causes a rapid increase in CSF hydrogen ion concentration. Increases in hydrogen ion concentration
sensed by the chemoreceptors result in increased
stimulation of the respiratory center and an increase
in ventilation.
5.13.2 The importance of CSF
bicarbonate
The chemoreceptors sense the hydrogen ion concentration in the brain ECF (or possibly some other
extracellular or intracellular compartment) but since
this cannot be sampled, the following discussion centers on the CSF acid-base changes which can be
measured. See below (section 5.15.1) for further

discussion of the differences between these two

compartments.
The Henderson-Hasselbalch equation, which
defines the relationship between PC02, bicarbonate
and pH (hydrogen ion concentration), is shown in
Figure 5.7. This indicates that for hydrogen ion
concentration to be held constant, a change of
bicarbonate concentration must be followed by a
change of Pcc,2 in the same direction. Assuming the
sensitivity of the central chemoreceptors to hydrogen
ion concentration remains constant, a reduction in
bicarbonate concentration will result in an increase
in hydrogen ion concentration which will stimulate
the central chemoreceptor and cause a rise in ventilation. This, in turn, will lower the PCOl and restore
the hydrogen ion concentration to normal, but now
with a lower PCo2- Thus a reduction in CSF
bicarbonate concentration has the effect of resetting
the chemoreceptor to start responding at a lower
PC02 (a shift to the left of the HCVR line). A rise in
CSF bicarbonate concentration has the opposite
effect and is seen in patients with chronic bronchitis
and hypercapnia. If the chemoreceptor responds to
log hydrogen ion concentration (i.e. pH), then
changes in Pcc,2 at low values, e.g. 20-21 mm Hg, will
have twice the effect as that at normal values, i.e.
40-41 mm Hg. This would then explain the steepening of the HCVR seen in acclimatized subjects.
These effects are shown in Figure 5.7. This is a
theoretical representation of the effect on HCVR of a
reduction in CSF bicarbonate concentration. A
typical HCVR line at sea level is shown on the right.
The CSF bicarbonate concentration is 24 mmol Ir1.
If the CSF bicarbonate concentration is reduced to

60 Ventilatory response to hypoxia and carbon dioxide

5.133 Reduction in CSF bicarbonate

concentration at altitude

Figure 5.7 Calculated effect of reducing CSF [HCO~3] on the HCVR

using the Henderson-Hasselbatch equation and assuming CSF pH
is held constant by ventilatory induced changes in PC02. V,
ventilation.

17 mmol L'1 the chemoreceptor now 'sees' an

increased hydrogen ion concentration and ventilation is stimulated until hydrogen ion concentration
is reduced to the previous value. The resulting Pcc,2
values are plotted and joined by a line giving the new
HCVR on the left. This looks very similar to the
actual effect of acclimatization on HCVR.
It is suggested that the mechanism of the change in
HCVR is a reduction in CSF bicarbonate concentration. Evidence for this is provided by the experiments
of Pappenheimer et al. (1964) in which they perfused
the cerebral ventricles of awake goats with artificial
CSF, varying the pH and bicarbonate concentration.
They showed that by simply reducing the bicarbonate
concentration in the CSF, the HCVR was shifted to
the left.
Bisgard et al. (1986) found evidence of the importance of CSF bicarbonate concentration in maintaining the residual ventilation of acclimatization on
giving normoxia. These workers perfused the carotid
body in awake goats with hypoxemic blood while the
rest of the animal, including the brain, was
normoxic. Carbon dioxide was added to the inspired
gas to maintain normocapnia despite hyperventilation. There was a time-dependent increase in
ventilation over the 4 h of the experiment, but since
brain and body were normocapnic and normoxic
there would have been no change in CSF bicarbonate
concentration. Full respiratory acclimatization did
not take place since, on switching the carotid
perfusion to normoxia, ventilation promptly fell to
normal.

In lowlanders going to an altitude of 3800 m the CSF

bicarbonate concentration is reduced from a mean
sea level value of 24.7 mmol L"1 to 20.4 mmol L"1 on
the second day at altitude and 20.1 mmol L~! on day
8 (Severinghaus et al. 1963). Similar results (mean
20.1 mmol L"1) were found at 4880 m (Lahiri and
Milledge 1967). Residents at high altitude had similar
values, 19.1-21.3 mmol L"1 (Severinghaus and
Carcelan 1964, Lahiri and Milledge 1967, Sorensen
and Milledge 1971). Thus the reduction in CSF
bicarbonate concentration of 4.5 mmol L"1 measured
at altitude sufficiently explains the shift of the HCVR
line to the left, though respiratory acclimatization
probably also involves contributions from other
mechanisms such as changes in the hypoxic ventilatory response (see section 5.5.1).

5.14
MECHANISMS FOR REDUCTION IN
CSF BICARBONATE CONCENTRATION
5*14.1

Possible mechanisms

Figure 5.8 shows three possible routes by which

hypoxia could cause a reduction in CSF bicarbonate
concentration. On the left is the 'classical' pathway.
Hypoxia stimulates the peripheral chemoreceptors
resulting in increased ventilation, decreased Pacc,2
and hence respiratory alkalosis. The kidneys respond
to the increased pH by excreting bicarbonate in the
urine, and plasma bicarbonate concentration falls. A
gradient develops for bicarbonate concentration
across the blood-brain barrier and CSF bicarbonate
concentration passes out slowly down the concentration gradient.
Severinghaus et al. (1963) reported that early in
altitude acclimatization their subjects had less
increase in CSF pH and a greater fall in CSF
bicarbonate concentration than in the plasma. Thus
bicarbonate appeared to pass out of the CSF against
the concentration gradient, suggesting active
transport of these ions out of, or hydrogen ion into,
the CSF. This mechanism is shown in the center of
the diagram (Figure 5.8).
On the right of Figure 5.8 is the third possible
mechanism for CSF bicarbonate concentration

Mechanisms for reduction in CSF bicarbonate concentration 61

Figure 5.8 Possible

mechanisms by which altitude
hypoxia could cause a
reduction in CSF [HCO~3]. PD,
potential difference.

reduction. With hypoxia there is a partial switch in

cerebral metabolism of glucose from the aerobic to
the anaerobic pathway. This results in formation of
lactic and pyruvic acids. The hydrogen ion produced
will directly buffer bicarbonate.
There is now abundant evidence supporting the
conclusions of Severinghaus et al. (1963) that CSF
acid-base changes are faster than renal compensation of plasma acid-base changes. Although the
latter may contribute to the later changes of
respiratory acclimatization, the major early changes
are largely complete in 24 h and have little to do with
renal compensation.

5.14.2 Active transport of CSF

bicarbonate concentration
Severinghaus's postulate of an active transport of
bicarbonate out of the CSF has stimulated a great

deal of work aimed at disproving or proving this

hypothesis. Fencl et al. (1966), using awake goats and
ventricular perfusion, also presented data supporting
the idea of active transport of bicarbonate out of the
CSF.
However, we must consider not only ionic
concentrations in blood and CSF but also the
electrical potential difference (PD) across the bloodbrain barrier. This PD between CSF and blood,
normally about +6.4 mV in dogs and +3 mV in
humans, becomes more positive as blood pH
increases (Bledsoe and Hornbein 1981). The change
is of the order of 32-53 mV per pH unit depending
on the type of acid-base change. Changes in CSF pH
do not affect PD. There is also a species difference in
the magnitude and even direction of change so that
extrapolation from experiments on animals to
humans must be made with caution. To complicate
the matter even further, PD is also affected by
changes in plasma potassium concentration.

62 Ventilatory response to hypoxia and carbon dioxide

5*14.3 Passive transport of CSF

bicarbonate concentration
Siesjo and Kjallquist (1969) proposed that the
apparent disequilibrium of hydrogen ion concentration and bicarbonate concentration across the
blood-brain barrier could be explained by these
changes in PD. That is, that shifts of these ions across
the barrier was by passive transport. Many papers
have addressed this problem and are reviewed by
Bledsoe and Hornbein (1981). Their conclusion is
that neither the active nor the passive transport
hypothesis is proven.

5.14.4 Cerebral tissue hypoxia and

lactacidosis
It is well known that hypoxia increases lactate (and
pyruvate) levels in the blood and CSF, and in their
paper proposing active transport of bicarbonate
Severinghaus et al. (1963) discussed the possibility
that increased lactic acid in the CSF might account
for the reduction in bicarbonate concentration.
However, the increase in lactate was only about
1 mmol L"1 compared with 4-5 mmol Ir1 reduction
in bicarbonate concentration. Lactic acid dissociates
to lactate and hydrogen ions in the cell. The two
species then pass through the cell membrane to
ECF, to CSF and across the blood-brain barrier,
probably with different rates at each stage. There is
no reason therefore to expect a simple one-to-one
relationship between their concentrations in the
CSF. In other words, production of hydrogen ion
from lactic acid might well be greater than is
indicated by the relatively small change in lactate
concentration.
There is evidence that hypoxia produces respiratory acclimatization independent of increased ventilation or decreased Pac02.
Eger et al. (1968) found that the effect of
hyperventilation on the position of the carbon
dioxide ventilatory response curve was greater
when subjects breathed a hypoxic mixture than
when they breathed air. This showed that
hypoxia had an effect independent of any change
in PCo2 Many high altitude residents having practically
no ventilatory response to acute hypoxia

nevertheless at altitude have Paco2, HCVR and

CSF bicarbonate concentration very similar to
lowlanders with a brisk HVR, indicating similar
respiratory acclimatization.
Sorensen and Mines (1970) showed that goats
that had had their carotid bodies denervated, so
that acute hypoxia actually depressed their
respiration, nevertheless showed a reduction in
PAC02 at altitude compared with sea level values.
In a companion study (Sorensen 1970) it was
shown that rabbits whose peripheral
chemoreceptors were denervated had a reduction
of CSF bicarbonate concentration similar to that
of controls when taken to altitude. Steinbrook et
al. (1983) also found evidence of good
respiratory acclimatization in goats with ablated
carotid bodies. However, in other studies in goats
(Lahiri et al. 1981, Smith et al. 1986) respiratory
acclimatization apparently did not take place in
the denervated animals, in that Pac02 did not fall
significantly. Certainly animals with denervated
or absent carotid bodies fare badly at altitude and
most studies reported a number of deaths
amongst their animals.
Fencl et al. (1979), in the awake goat with
perfused ventricles, showed that in the
acclimatized animal lactate was higher and
bicarbonate concentration lower in the brain
ECF than in the CSF (at sea level there was no
concentration difference).
These lines of evidence suggest that hypoxia per se
has a role in respiratory acclimatization, presumably
by its effect on cerebral metabolism.

5.15
5.15.1

BRAIN ACID-BASE BALANCE

Brain extracellular fluid

In the foregoing sections CSF pH has been discussed

because that was what had been measured in the
studies quoted. However, it must be remembered
that the central chemoreceptor senses the hydrogen
ion concentration in the fluid in its immediate
vicinity, the local brain ECF. It has been calculated
from studies in awake goats perfused with artificial
CSF (Pappenheimer et al. 1964) that in the steady
state this represents a point about three-quarters of
the way along the concentration gradient for

Dynamic carbon dioxide response 63

hydrogen ion and bicarbonate between CSF and

plasma.
In a situation of changing acid-base balance, as for
instance the developing respiratory alkalosis on
going to altitude, the local brain ECF will change
more rapidly than the bulk CSF. This is especially the
case for respiratory as compared with metabolic
changes. Within a few seconds of a fall in brain -PCo2>
brain bicarbonate concentration falls. The buffering
capacity for brain ECF is greater by a third than the
CSF so the compensation for pH change is faster and
greater in this compartment than in the CSF
(Dempsey and Forster 1982).
It must also be remembered that the brain ECF is
affected by cerebral blood flow so that changes in
Pa02 and -Pac02 will have secondary effects by
changing cerebral blood flow. This makes interpretation of studies even more difficult.
5.15.2

The lack of stability of CSF pH

Since the sensitivity to PC02 is via the pH-sensitive

central chemoreceptors and since Pacc,2 is so closely
regulated, it seemed reasonable to assume that CSF
pH was extremely stable. At sea level a fall of pH of
about 0.03 pH units results in a doubling of the resting ventilation. Even when this is converted to a
change of hydrogen ion concentration concentration, it represents an increase of only 7 per cent. Thus
we have a negative feedback loop of very high gain,
suggesting very tight regulation of pH.
However, in fact during acclimatization the CSF
pH rises by about 0.03-0.06 units while ventilation
goes up. The reverse happens with acute normoxia
(Dempsey and Forster 1982). The change in pH is, of
course, much less than would have occurred without
the change in bicarbonate concentration, as discussed in section 5.13.3. There are three possible
explanations for this paradoxical change of CSF pH:
The drive from peripheral chemoreceptors is
sufficient to increase ventilation even when the
central drive is reduced. In subjects with a brisk
HVR this is the most important cause of CSF
alkalosis.
The brain ECF may well be different from the
bulk CSF in respect of hydrogen ion
concentration and bicarbonate concentration
(see section 5.15.1), so that cerebral lactacidosis
causes higher hydrogen ion concentration in

brain ECF than in CSF. This is suggested by the

work on awake goats with perfused ventricles at
altitude (FendetaL 1979).
The effect of acute hypoxia on cerebral blood flow
was studied by Crawford and Severinghaus
(1978), who calculate that, at an altitude of
3810 m, hypoxia causes a 30 per cent rise in blood
flow to the central chemoreceptor area, resulting
in a rise in pH of 0.006 units. Acute normoxia
causes a similar, though opposite, change.
These effects would seem to account for most of
the 'negative correlation' of hydrogen ion concentration with ventilation pointed out by Dempsey et
al. (1979). It is not necessary to invoke any change in
sensitivity of the central chemoreceptor to hydrogen
ion concentration, although this cannot be ruled out.
Thus, it would seem that CSF pH is the result of the
combined effects of peripheral and central drive and
is not, in fact, very tightly controlled. Where
peripheral drive is strong, as in lowlanders at
altitude, the CSF pH is increased. Where peripheral
drive is low, as at sea level, highlanders and even
more in subjects with denervated carotid bodies, CSF
pH is reduced.

5*153

Brain intracellular pH

Using magnetic resonance spectroscopy on unacclimatized lowland subjects in a hypobaric

chamber, Goldberg et al. (1992) found that, after a
week at 4267 m simulated altitude, there was no
significant change in intracellular pH although on
return to normobaria there was a significant intracellular acidosis.

5.16
DYNAMIC CARBON DIOXIDE
RESPONSE
Carbon dioxide is eliminated only during expiration;
during inspiration it is retained. Therefore the level
of carbon dioxide in the blood leaving the lungs must
oscillate in time with breathing. During exercise
these oscillations will be increased. Yamamoto and
Edwards (1960) suggested that these oscillations
might be a signal to which the peripheral chemoreceptors could respond over and above the mean
level of carbon dioxide in the arterial blood. The

64 Ventilatory response to hypoxia and carbon dioxide

response to this putative signal of change in carbon

dioxide with time is called the dynamic carbon
dioxide ventilatory response. Datta and Nickol
(1995) showed that this response could be demonstrated in exercising humans (it had been shown
previously in anesthetized cats) by measuring the
ventilation during the injection of a small bolus of
carbon dioxide either early or late in inspiration.
Ventilation was found to be greater with early pulses.
Collier et al (1995) showed that this response is
absent in acute hypoxia and weak or absent on first
arrival at altitude. It is enhanced with acclimatization
and is greatest in subjects who have climbed to over
7000 m. This provides evidence that the ventilatory
response of the peripheral chemoreceptor is
increased for carbon dioxide as it is for hypoxia
(section 5.5.1).

5.17
5.17.1

LONGER TERM ACCLIMATIZATION

Highlanders

People native to high altitude have lower ventilation

and higher Pac02 than acclimatized newcomers
(Chiodi 1957). This is probably due to their blunted
HVR (see section 5.5.2). The HCVR of Andean
natives (Severinghaus et al. 1966a), Sherpas
(Milledge and Lahiri 1967) and Tibetans (Shi et al.

1979) has the same slope as that of lowlanders at the

same altitude. The position of the carbon dioxide
ventilatory response line may be to the right
(Severinghaus et al. 1966a) or not significantly
different from lowlanders (Milledge and Lahiri
1967). That is, there is little difference between
highlanders and lowlanders in their carbon dioxide
ventilatory response.
5.17.2

Lowlanders

Although most of the respiratory acclimatization

takes place within the first few hours and days at
altitude, there may be further changes over the
following weeks. In humans, there is a further
increase in ventilation and Pa02 with a further
decrease in .Pac02 (Forster et al. 1974), though in
other animals, e.g. pony and goat, the Pac02 reaches
the lowest point at 8-12 h and then rises. The rat
responds like humans with continued fall in Pacc,2
up to 14 days (Dempsey and Forster 1982). There
is no significant change in acid-base balance over
this period to account for this further ventilatory
adaptation. It is likely that there is an increase in
sensitivity of the carotid body over this period (see
section 5.5.1) and it is possible that changes in
control from higher centers, such as have been
demonstrated in cats by Tenney and Ou (1977),
may be responsible.

6
Lung diffusion
6.1
6.2
6.3
6.4

Introduction
Historical
Physiology of diffusion in the lung
Pulmonary diffusing capacity at
high altitude

65
66
67
74

SUMMARY
Diffusion of oxygen across the blood-gas barrier is a
critical link in the oxygen cascade from the atmosphere to the mitochondria. In fact, exercise at high
altitude is one of the few situations where oxygen
transfer is diffusion limited in normal humans. On a
historical note, up to the 1930s some physiologists
believed that the lung secreted oxygen, but we now
believe that all gases pass across the blood-gas barrier
by passive diffusion. The distinction between a perfusion limited and diffusion limited gas such as carbon monoxide is emphasized. Diffusion across the
blood-gas barrier is enhanced if the oxygen affinity
of the hemoglobin is increased. This occurs in many
animals that live in oxygen-deprived environments,
and interestingly, the oxygen affinity of hemoglobin
is greatly increased at extreme altitude because of the
severe respiratory alkalosis. Lowlanders who go to
high altitude have a small increase in the diffusing
capacity of the lung for carbon monoxide but this
can be explained by the polycythemia and the
increased rate of reaction of carbon monoxide with
hemoglobin as a result of the reduced P02. Several
studies show that high altitude natives have higher
diffusing capacities than similar people at sea level. A
possible explanation is the accelerated growth of the
lung that occurs in a hypoxic environment. Diffusion

6.5
6.6

Diffusion limitation of oxygen transfer at

high altitude
Diffusion in the placenta at high altitude

76
80

limitation of oxygen transfer at extreme altitude,

particularly on exercise, exaggerates the already
severe hypoxemia. A relatively high diffusing capacity of the lung probably improves work capacity at
very high altitudes.

6.1

INTRODUCTION

Diffusion refers to the process by which oxygen

moves from the alveolar gas into the pulmonary capillary blood, and carbon dioxide moves in the reverse
direction. That this step in the cascade of oxygen
transfer from the air to the mitochondria might be a
limiting factor at high altitude was suggested near the
beginning of the twentieth century. However, it is
only since about 1980 that the role of diffusion at
high altitude has been clearly elucidated.
Diffusion as defined above refers to the movement
of oxygen in solution through the tissues of the
blood-gas barrier, and for convenience we also
include the delay caused by the chemical combination of oxygen with hemoglobin in the pulmonary
capillary blood (section 6.3.4). The term diffusion is
also used in another context in the lung, that is the
transport of gas in the small airways by the random
movement of molecules in the gas phase. This
process plays an important role in the movement of

66 Lung diffusion

oxygen from the terminal bronchioles to the alveoli.

It is unlikely that this process ever limits oxygen
transfer in the normal lung at sea level, though the
issue cannot be considered completely settled. At
high altitude, diffusion in the gas phase becomes
even less likely as a potential limiting factor because
the mean free path of the molecules is increased as a
result of the rarefaction of the gas. Consequently, diffusion in the gas phase will not be considered further.

6.2

HISTORICAL

The role of diffusion in the lungs was a topic of great

controversy among respiratory physiologists in the
last decade of the nineteenth century and the first
two decades of the twentieth, and the arguments
specifically involved the issue of diffusion at high
altitude. Paradoxically much of the disagreement was
generated by physiologists who contended that passive diffusion was not the primary mechanism of
oxygen transfer through the blood-gas barrier, but
that this process was achieved by active secretion. By
this they meant that oxygen could be moved from a
region of low partial pressure to one of high partial
pressure as a result of some active process in the
epithelial cells which required energy.
One of the strongest proponents of the secretion
hypothesis was the Danish physiologist Christian
Bohr. In a paper published in 1891 he compared the
P02 and PC02 of alveolar gas with that of gas in a
tonometer equilibrated with arterial blood taken at
the same time. In some instances the alveolar P02 was
reported to be as much as 30 mm Hg below, and the
PCo2 as much as 20 mm Hg above, the arterial blood
values. Bohr's conclusion was:
In general, my experiments have shown definitely
that the lung tissue plays an active part in gas
exchange; therefore, the function of the lung can
be regarded as analogous to that of the glands
(Bohr 1891).

Bohr referred to the secretion ability of the lung as

its 'specific function'. In 1909 he published a long
paper on this topic, claiming that the active secretion
of oxygen and carbon dioxide could use large
amounts of oxygen, up to 60 per cent of the total
requirements of the body. If this were true, the Pick
principle for deriving cardiac output from the

oxygen consumption measured at the mouth would

be invalid. Although the first part of his paper was
devoted to active secretion, the second analyzed the
basic principles of oxygen diffusion through the
bloodgas barrier. Here Bohr introduced the mathematical process which is now known as the 'Bohr
integration'. It forms the basis for modern calculations of the time course of oxygen transfer from the
alveolar gas into the blood as it moves along the pulmonary capillary (Bohr 1909).
August Krogh was one of Bohr's students and
assisted him in his experiments on gas secretion from
1899 to 1908. Krogh gradually became persuaded
that passive diffusion rather than active secretion
could account for the experimental data and in 1910
published a landmark paper on this topic. Since Bohr
was his major professor and very jealous of the secretion theory, the introductory section of Krogh's
paper required an unusually delicate touch. Part of it
reads:
I shall be obliged in the following pages to combat
the views of my teacher Prof. Bohr on certain essential points and also to criticize a few of his experimental results. I wish here not only to acknowledge
the debt of gratitude which I, personally, owe to
him, but also to emphasize the fact, patent to
everybody, who is familiar with the problems here
discussed, that the real progress, made during the
last twenty years in the knowledge of the processes
in the lungs, is mainly due to his labours... (Krogh
1910).

The British physiologist J. S. Haldane visited Bohr

in Copenhagen and also became convinced of the
secretion theory, at least as far as oxygen was concerned. For example, in 1897 Haldane and Lorraine
Smith wrote: 'The absorption of oxygen by the lungs
thus cannot be explained by diffusion alone'
(Haldane and Smith 1897). Haldane argued that
oxygen secretion would be particularly beneficial at
high altitudes, and in order to test the hypothesis the
Anglo-American expedition to Pikes Peak was organized in 1911. Arterial P02 was calculated by an indirect method following the inhalation of carbon
monoxide, and the results appeared strongly to support the secretion hypothesis.
However, the theory was also attacked by Marie
Krogh (wife of August) when she developed a
method for measuring the diffusing capacity of the
lung using small concentrations of carbon monoxide

Physiology of diffusion in the lung 67

(Krogh and Krogh 1910). Her results indicated that

the normal lung was capable of transferring very
large amounts of oxygen by passive diffusion even
when the inspired P02 was greatly reduced.
Various measurements in low pressure chambers
and during climbs to great altitudes were used as evidence to support one or other of the two camps. For
example, Zuntz and his co-workers made some measurements in the first high altitude research station,
the Capanna Regina Margherita on the Monte Rosa
in the Italian Alps, and Bohr used the results as evidence for active secretion of oxygen. In this experiment, the oxygen consumption of one subject was
1.52 L min"1 when the alveolar P02 was only 57 mm Hg
(Zuntz et al. 1906, Appendix Tables XI and XVIII).
Bohr had just described his mathematical integration
procedure and he claimed that the experimental data
were inconsistent with passive diffusion being the
only mode of oxygen transfer (Bohr 1909).
In the same year that Bohr's paper appeared, the
Duke of Abruzzi reached the extraordinary altitude
of 7500 m in the Karakoram mountains without supplementary oxygen. This was an astonishing climb
because only a few years before, experienced alpinists
had reported that 21 500 ft (6500 m) was 'near the
limit at which man ceases to be capable of the slightest further exertion' (Hinchliff 1876, p. 91). Indeed
one of the reasons given for the Duke's expedition
was 'to see how high man can go' (Filippi 1912).
Douglas, Haldane and their co-workers were duly
impressed by the Duke's achievement and estimated
from the reported barometric pre'ssure of 312 mm Hg
that the alveolar P02 was only 30 mm Hg. They therefore concluded that adequate oxygenation of the arterial blood would be impossible under these
conditions without active secretion (Douglas et al.
1913). However, this conclusion was disputed by
Marie Krogh (1915) who argued that Douglas and his
colleagues had markedly underestimated the diffusing capacity of the lung. Incidentally we now know
that Douglas et al.'s estimate of an alveolar P02 of
30 mm Hg for a barometric pressure of 312 mm Hg
was much too low; the actual value is approximately
35 mm Hg (Gill et al. 1962) in a region of the oxygen
dissociation curve where an increase of 5 mm Hg
makes a world of difference.
Another physiologist who did not accept the secretion story was Joseph Barcroft. He conducted a
heroic experiment on himself by living in a sealed
glass chamber filled with hypoxic gas for 6 days

(Barcroft et al. 1920). His left radial artery was

exposed 'for an inch-and-a-half and blood was taken
for measurements of oxygen saturation. There was a
'somewhat dramatic moment' when the first blood
sample was drawn because it 'looked dark', an observation which was believed to be inconsistent with
oxygen secretion. The conclusion was that diffusion
was the only mechanism necessary for oxygen transfer across the blood-gas barrier during hypoxia.
Barcroft and his colleagues subsequently tested the
secretion hypothesis further on their expedition to
Cerro de Pasco in the Peruvian Andes in 1921-2. The
diffusing capacity of the lung for carbon monoxide
was measured on five members of the expedition
both at sea level and at Cerro de Pasco, and only a
small increase was found. Barcroft therefore argued
that the tendency for the arterial oxygen saturation
to fall during exercise at high altitude could be
explained by the failure of equilibration of P02
between alveolar gas and pulmonary capillary blood
(Barcroft et al. 1923). This was one of the first direct
demonstrations of diffusion limitation, a finding that
has been confirmed many times since.
It is remarkable that J. S. Haldane remained a
staunch supporter of oxygen secretion all his life. In
the second edition of his book Respiration, written
with J. G. Priestley and published in 1935, a year
before Haldane's death, a whole chapter was devoted
to evidence for oxygen secretion (Haldane and
Priestley 1935). Haldane gradually shifted his position as evidence mounted against the secretion
hypothesis. He initially thought that oxygen secretion occurred under all conditions, but later argued
that it only became significant at high altitude, and
later still that it required a period of acclimatization.
His obsession with this theory long after seemingly
overwhelming evidence had been provided against it
was remarkable in this great physiologist.

63
PHYSIOLOGY OF DIFFUSION IN THE
LUNG
6*3.1

Anatomical basis

The structure of the human lung is well suited to its

role of allowing passive diffusion of oxygen from the
alveolar gas to the interior of the red blood cell. The
blood-gas barrier is extremely thin, being only

68 Lung diffusion

0.2-0.3 p,m in many places, and the area of the

blood-gas barrier available for diffusion is
50-100 m2.
Figure 6.1 shows an electron micrograph of a pulmonary capillary and emphasizes the short distance
over which oxygen diffuses in (or carbon dioxide diffuses out). The various tissues through which oxygen
moves are: layer of surfactant (not shown in this
preparation because of the method of fixation), type
1 alveolar epithelial cell (EP), interstitium (IN)
(often much thinner on one side of the capillary than
the other, as in the figure), capillary endothelial cell
(EN), plasma and red cell. Note that the path length
through the blood-gas barrier itself is only a small
fraction of the total diffusion distance from the alveolar gas to the center of the red cell.
Recently, several morphometric studies have been

made of the pulmonary blood-gas barrier in humans

and other animals. Since the diffusion rate of a gas
through a tissue slice is inversely proportional to its
thickness, the appropriate variable to be calculated
for diffusion resistance is the harmonic mean of the
width of the blood-gas barrier. An intriguing feature
of these studies is that the calculated pulmonary diffusing capacity for the human lung is apparently
higher than that found experimentally. For example,
Gehr and his colleagues (1978) calculated a maximum diffusing capacity in the human lung of
263 mL min~' mm Hg~' by morphometry whereas the
maximum values found experimentally are generally
less than half of this (Riley et al. 1954, Shepard et al.
1958, Turino et al. 1963, Haab et al. 1965). The discrepancy may be related to artifacts of the morphometric techniques, for example assuming that all the
pulmonary capillaries can take part in gas exchange
at any instant of time, whereas in practice some of
them may not be recruited even during maximum
exercise. However, it should be noted that the measurement of the pulmonary diffusing capacity for
oxygen is difficult and indeed some estimates have
given values which are closer to the morphometric
range (Wagner et al. 1987). Nevertheless, there still
appears to be a disparity between the anatomical and
functional estimates.

63.2

Figure 6.1 Electron micrograph showing a pulmonary capillary (C)

in the alveolar wall. Note that in many places, the thickness of the
blood-gas barrier is less than 0.5 \im. The large arrow shows the
diffusion path from the alveolar gas to the interior of the red blood
cell (EC) and includes the alveolar epithelium (EP), interstitium (IN),
and the capillary endothelium (EN), (these are grouped as (2) in the
figure), plasma (3), and red blood cell (4). Other labeled structures
include fibroblasts (FB) and the basement membrane (BM). (From
Weibel 1970.)

Pick's law of diffusion

Pick's law of diffusion states that the rate of transfer

of a gas through a sheet of tissue is proportional to
the area of the tissue and to the difference in gas partial pressure between the two sides, and inversely
proportional to the tissue thickness. As indicated
above, the area of the blood-gas barrier in the human
lung is some 50-100 m2, and the thickness is less than
0.3 Jim in many places, so the dimensions of the barrier are well suited to diffusion.
In addition, the rate of gas transfer is proportional
to a diffusion constant which depends on the properties of the tissue and the particular gas. The constant
is proportional to the solubility of the gas and
inversely proportional to the square root of its molecular weight. This means that carbon dioxide diffuses
about 20 times more rapidly than oxygen through
tissue sheets since its solubility is about 24 times
greater at 37 C and the molecular weights of carbon
dioxide and oxygen are in the ratio of 1.375 to 1.

Physiology of diffusion in the lung 69

Pick's law can be written as

where V" is volume per unit time, A is area, T is thickness, D is the diffusion constant, and P, and P2
denote the two partial pressures.
For a complex structure such as the blood-gas
barrier of the human lung, it is not possible to measure the area and thickness during life. Instead, we
combine A, T and D and rewrite the equation as

where DL is the diffusing capacity of the lung.

The gas of choice for measuring the diffusing
capacity of the lung is carbon monoxide (at very low
concentrations) because the avidity of hemoglobin
for this gas is so great that the partial pressure in the
capillary blood is extremely small (except in smokers) and thus the uptake of the gas is solely limited by
the diffusion properties of the blood-gas barrier.
(The complication caused by finite reaction rates is
considered below.) Thus if we rewrite the above
equation as

where Pj and P2 are the partial pressures of alveolar

gas and capillary blood respectively, we can set P2 to
zero. This leads to the equation for measuring the
diffusing capacity of the lung for carbon monoxide:

In words, the diffusing capacity of the lung for carbon monoxide is the volume of carbon monoxide
transferred in mL min'1 mm Hg-1 of alveolar partial
pressure.

63.3
Measurement of diffusing
capacity
Several techniques can be used for measuring the diffusing capacity of the lung for carbon monoxide. The
popular single breath method is essentially a modification of that originally suggested by Marie Krogh
(1915). The subject makes a vital capacity inspiration
of a very dilute mixture of carbon monoxide, and the

rate of its disappearance from alveolar gas during a

10s breath-hold is calculated. This is often done by
measuring the inspired and expired concentrations
of carbon monoxide with an infrared analyzer. The
alveolar concentration of carbon monoxide is not
constant during the breath-holding period but
allowance can be made for that; it is assumed that its
disappearance is exponential with time. Helium is
also added to the inspired gas so that by its dilution
the lung volume in which the single breath has mixed
can be calculated.
In the steady-state carbon monoxide method, the
subject breathes a low concentration of the gas
(about 0.1 per cent) for 30 s or so until a steady state
of uptake has been reached. The constant rate of disappearance of carbon monoxide from alveolar gas is
then measured for a further short period along with
the alveolar concentration. The normal value of the
diffusing capacity for carbon monoxide at rest is
about 25 mL min^1 mm Hg"1, and it increases to two
or three times this value on exercise.
The measurement of the diffusing capacity for
oxygen in humans is much more difficult. An early
method was to measure the alveolar-arterial P02 difference during severe hypoxia (Riley et al. 1954,
Shepard et al. 1958) but it is difficult to remove the
contribution caused by ventilation/perfusion
inequality. Another technique is to use an isotope of
oxygen, for example oxygen-18 (Hyde et al. 1966).
Other measurements have been made in experimental animals during severe hypoxia, assuming linearity
of the oxygen dissociation curve, but this may introduce significant errors.
All methods of measuring pulmonary diffusing
capacity are affected by the presence in the lung
of ventilation/perfusion and diffusion/perfusion
inequalities. No satisfactory way of allowing for these
sources of error has yet been devised. However, studies using the multiple inert gas elimination technique
can separate the hypoxemia caused by diffusion limitation from that due to ventilation/perfusion
inequality (section 6.5).

63.4

Reaction rates with hemoglobin

Early workers assumed that all of the resistance to the

transfer of oxygen from the alveolar gas into the capillary blood could be attributed to the diffusion
process within the blood-gas barrier. However,

70 Lung diffusion

when the rates of reaction of oxygen with hemoglobin were measured using a rapid reaction apparatus, it became clear that the rate of combination with
hemoglobin might also be a limiting factor. If oxygen
is added to deoxygenated blood, the formation of
oxyhemoglobin is quite fast, being well on the way to
completion in 0.2 s. However, oxygenation occurs so
rapidly in the pulmonary capillary that even this
rapid reaction significantly delays the loading of oxygen by the red cells. Thus the uptake of oxygen can be
regarded as occurring in two stages:
diffusion of oxygen through the blood-gas barrier
(including the plasma and red cell interior)
reaction of the oxygen with hemoglobin (Figure
6.2).
In fact it is possible to sum the two resulting resistances to produce an overall resistance (Roughton
and Forster 1957).
We saw above that the diffusing capacity of the
lung is defined as

that is, as the flow of gas divided by the pressure difference. It follows that the inverse of DL is pressure
difference divided by flow and is therefore analogous
to electrical resistance. Consequently the resistance
of the blood-gas barrier in Figure 6.2 is shown as
1/DM where M denotes membrane. The rate of reaction of oxygen with hemoglobin can be described by
6, which gives the rate in mL min"1 of oxygen which

Figure 6.2 How the measured diffusing capacity of the lung (DL)
is made up of two components, one due to the diffusion process
itself (DJ, and one attributable to the time take for oxygen to
react with hemoglobin (QVJ.

combine with 1 mL blood mm Hg"1 P0r This is

analogous to the 'diffusing capacity' of 1 mL of blood
and, when multiplied by the volume of capillary
blood (Vc), gives the effective 'diffusing capacity' of
the rate of reaction of oxygen with hemoglobin.
Again its inverse, 17(0^), describes the resistance of
this reaction.
It is possible to add the resistances offered by the
membrane and the blood to obtain the total resistance. Thus the complete equation is

In practice the resistances offered by the membrane and blood components are approximately
equal in the normal lung.

63.5
Rate of oxygen uptake along the
pulmonary capillary
By using Pick's law of diffusion, and data on reaction
rates of oxygen with hemoglobin, it is possible to calculate the time course of P02 along the pulmonary
capillary as the oxygen is loaded by the blood. The
application of Pick's law to this situation is not trivial
because of the chemical bond which forms between
oxygen and hemoglobin. This means that the relationship between P02 and oxygen concentration in
the blood is nonlinear, as shown by the oxygen dissociation curve. This problem was first solved by Bohr
(1909) and the numerical integration procedure
which he developed is known as the Bohr integration. A further complication occurs because, as oxygen is being taken up, carbon dioxide is given off,
and this alters the position of the oxygen dissociation
curve. A full treatment of this latter process should
take into account not only the rate of diffusion of
carbon dioxide through the blood-gas barrier, but
also the rates of reaction of carbon dioxide in blood.
Since not all the rate constants are known under all
the required conditions, some assumptions and simplifications are necessary.
Figure 6.3 shows a typical time course calculated
for the lung of a resting subject at sea level (Wagner
and West 1972, West and Wagner 1980). The diffusing capacity of the blood-gas barrier itself (DM) was
assumed to be 40 mL min"1 mm Hg"1, and the time
spent by the blood in the pulmonary capillary was
taken as 0. 75 s (Roughton 1945). Other assumptions

Physiology of diffusion in the lung 71

Figure 6.4 Calculated time course of the P02 along the pulmonary
capillary for a climber at rest on the summit of Mount Everest.
Note that there is considerable diffusion limitation of oxygen
Figure 6.3 Calculated time course for P<,2 in the resting human
pulmonary capillary at sea level. Note that there is ample time for

uptake with a large alveolar end-capillary P02 difference. PB 253

mm Hg; \2 350 mL min~1 (From West et al. 1983b.)

equilibration of the P02 between alveolar gas and end-capillary

blood. V02 300 ml min-1; DM02 40 mi min-1 mm Hg-1. (From West
and Wagner 1980.)

include a resting cardiac output of 6 L min"1 and

oxygen uptake of 300 ml mkr1.
Note that the blood comes into the lung with a P02
of 40 mm Hg and the P02 rapidly rises to almost the
alveolar P02 level by the time the blood has spent only
about one-third of its available time in the capillary.
The rate of rise of P02 in the latter two-thirds of the
capillary is extremely slow, and there is a negligible
P02 difference between alveolar gas and end-capillary
blood.
This time course can be contrasted with that calculated for a resting climber breathing air on the
summit of Mount Everest (Figure 6.4). Again, the
membrane diffusing capacity of the blood-gas barrier was assumed to be 40 mL min"1 mm Hg"1 based
on measurements made on acclimatized lowlanders
at an altitude of 5800 m (West 1962a). The oxygen
uptake was taken to be 350 mL min"1, and other
blood and alveolar gas variables were taken from
measurements made on the American Medical
Research Expedition to Everest (West et al. 1983b).
The time spent by the blood in the pulmonary capillary was assumed to be unchanged at 0.75 s because
this is determined by the ratio of capillary blood

volume to cardiac output (Roughton 1945). The capillary blood volume was shown to be unchanged at
5800 m (West 1962a), and the cardiac output is also
the same as at sea level according to the measurements of Pugh (1964c) (Chapter 7).
It can be seen that the oxygen profile is very different at this extreme altitude. The blood comes into the
lung with a P02 of only about 21 mm Hg, and the P02
rises very slowly along the pulmonary capillary,
reaching a value of only 28 mm Hg at the end. Thus
there is a large P02 difference of some 7 mm Hg
between alveolar gas and capillary blood. This indicates marked diffusion limitation of oxygen transfer.
It can be shown that this diffusion limitation
becomes more striking as the oxygen consumption is
increased by exercise.
The very different time courses for P02 shown in
Figures 6.3 and 6.4 represent the extremes between
sea level and the highest point on Earth for resting
humans. At intermediate altitudes, the difference
between alveolar and end-capillary P02 will be considerably reduced at rest and may be negligibly small.
However, exercise will always tend to increase the
alveolar end-capillary P02 difference.
Whether carbon dioxide elimination is ever
limited by diffusion is still unknown. This is
partly because some of the reaction rates of car-

72 Lung diffusion

bon dioxide in blood remain uncertain. Many

physiologists believe that some diffusion limitation of carbon dioxide output may occur during
heavy exercise.

63*6 Diffusion and perfusion

limitation of oxygen transfer
It is clear from Figure 6.3 that a resting subject at
sea level has no diffusion limitation of oxygen
transfer because there is no P02 difference between
alveolar gas and end-capillary blood. Under these
conditions, the amount of oxygen which is taken
up by the blood is determined by the pulmonary
blood flow. This means that oxygen uptake is perfusion limited.
By contrast, Figure 6.4 shows a situation where
oxygen uptake is, in part, diffusion limited. This is
indicated by the large P02 difference between alveolar
gas and end-capillary blood. However, under these
conditions, oxygen uptake is also partly perfusion
limited because increasing pulmonary blood flow
will increase oxygen uptake.
The conditions under which diffusion and perfusion limitation occur have been clarified by Piiper
and Scheid (1980). They used a simplified model
with several assumptions including linearity of the
oxygen dissociation curve in the working range. This
is approached during conditions of severe hypoxia
when the lung is operating very low on the oxygen
dissociation curve, though even here it can be shown

that the rapid elimination of carbon dioxide in the

early part of the capillary substantially increases the
slope of the oxygen dissociation curve (West 1982b).
This introduces appreciable errors; nevertheless, the
model is valuable conceptually.
Using this simplified model, Piiper and Scheid
showed that the total transfer rate M of a gas is given
by the expression:

where PA and Pv are the partial pressures of oxygen

in the alveolar gas and venous blood respectively, Q
is cardiac output, D is the diffusing capacity, and P
is the slope of the oxygen dissociation curve
(assumed to be linear). The total conductance G for
gas exchange between alveolar gas and capillary
blood may be defined as the transfer rate divided by
the total effective partial pressure difference (PA Pv), or

This expression clarifies the factors responsible for

diffusion and perfusion limitation. The equation
shows that if D is very much larger than Q (3, the
expression inside the large brackets tends to 1, and
gas transfer is limited by perfusion only. In this case,
the (perfusive) conductance is given by G = Q(3. The
relative difference between the conductance without
diffusion limitation and the actual conductance is an
index of diffusion limitation, Ldiff in Figure 6.5.
By contrast, diffusion limitation occurs if Q(3 is so

Figure 6.5 Conditions under which

diffusion limitation of gas transfer in
the lung occurs. Ldiff is a measure of
diffusion limitation; when its value is
1.0, gas transfer is entirely diffusion
limited. It can be seen that Ldiff is
greatest for carbon monoxide, and
least for oxygen under hyperoxic
conditions. D, diffusing capacity; Q,
pulmonary blood flow; |3, solubility of
the gas in blood, or slope of its
dissociation curve. See text for details.
(Modified from Piiper and Scheid
1980.)

Physiology of diffusion in the lung 73

large that it greatly exceeds D, or to put it in another

way, D becomes relatively very small. In this case the
(diffusive) conductance is given by G = D. The relative difference between the conductance without
perfusion limitation and the actual conductance is an
index of perfusion limitation. Zero on the vertical
axis of Figure 6.5 indicates complete perfusion limitation.
Figure 6.5 shows that oxygen uptake is entirely
perfusion limited in hyperoxia (extreme right of diagram) and that this is also true for the uptake of the
inert gases nitrogen and sulfur hexafluoride.
However, oxygen transfer during hypoxia becomes
diffusion limited to some extent (middle of diagram)
and this is particularly the case during exercise when
oxygen consumption is greatly increased. For carbon
monoxide, gas transfer is essentially diffusion limited
under all conditions (left of diagram).
The above analysis emphasizes that an important
factor leading to diffusion limitation is an increase in
(3, that is the slope of the blood-gas dissociation
curve. This is the reason why the uptake of carbon
monoxide is entirely diffusion limited; the slope of its
dissociation curve is extremely large. An increased
slope of the oxygen dissociation curve tending to diffusion limitation occurs for three reasons at high altitude:
First, the lung is working on a low part of the oxygen dissociation curve which is very steep.
Secondly, the polycythemia of high altitude
increases the change in blood oxygen concentration per unit change in P0r
Thirdly, the left shift of the curve caused by the
respiratory alkalosis increases its slope. In fact, at
extreme altitude, oxygen begins to resemble carbon monoxide to some extent.
For readers who prefer an intuitive explanation
to the more formal analysis given above, the essential conclusion can be stated as follows. Diffusion
limitation is likely when the 'effective solubility' of
the gas in pulmonary capillary blood (that is, the
slope of the dissociation curve) greatly exceeds the
solubility of the gas in the tissues of the blood-gas
barrier. This condition is met for carbon monoxide
for which blood has an enormous avidity, and is
approached for oxygen at high altitude because of
the steepness of its dissociation curve at low P02
values, and the increased blood hemoglobin concentration.

6,3.7 Oxygen affinity of hemoglobin

and diffusion limitation
It can be shown that increasing the affinity of hemoglobin for oxygen expedites the loading of oxygen in
the pulmonary capillary under conditions of diffusion limitation at high altitude. The oxygen affinity
of hemoglobin is conveniently expressed by the P50,
that is the P02 for 50 per cent saturation of the hemoglobin. The normal value is about 27 mm Hg.
Numerical analysis shows that increasing the
affinity (leftward shift of the oxygen dissociation
curve) results in more rapid equilibration between
the P02 of alveolar gas and pulmonary capillary
blood. A simplified way of looking at this is that the
left-shifted curve keeps the blood P02 low in the initial stages of oxygen loading and thus maintains a
large P02 difference between alveolar gas and capillary blood during much of the oxygenation time.
This increased P02 difference therefore maintains the
driving pressure and accelerates loading.
However, a left-shifted oxygen dissociation curve
interferes with the unloading of oxygen in peripheral
capillaries because, for a given P02 in venous blood
(required to maintain the diffusion head of pressure
to the tissues), the blood unloads less oxygen. It is
therefore not intuitively obvious whether the advantages of a left-shifted curve in assisting the loading of
oxygen in the pulmonary capillaries outweigh the
disadvantages of unloading the oxygen in the peripheral capillaries.
Several pieces of evidence suggest that a high oxygen affinity of hemoglobin is beneficial under
hypoxic conditions. For example, the llama and
vicuna, animals native to the Peruvian highlands,
have left-shifted oxygen dissociation curves (Figure
6.6), as do some burrowing animals whose environment becomes oxygen depleted (Hall et al. 1936).
The human fetus, which is believed to have arterial
P02 in the descending aorta of less than 25 mm Hg,
has a greatly increased oxygen affinity by virtue of its
fetal hemoglobin which has a P50 at pH 7.4 of about
17 mmHg. Experimental studies have shown that
rats with artificially left-shifted oxygen dissociation
curves tolerate severe acute hypoxia better than rats
with normal dissociation curves (Eaton et al. 1974).
Again, Hebbel and his colleagues (1978) described a
family in which two of the four children had an
abnormal hemoglobin (Andrew-Minneapolis) with
a P50 of 17 mm Hg. These two siblings had a higher

74 Lung diffusion

Figure 6.6 Oxygen dissociation curves for blood of llama (O) and
vicuna (AJ compared with other mammals. The left-shifted curve
for these high altitude native animals indicates an increased
affinity of the hemoglobin for oxygen which assists in oxygen
loading along the pulmonary capillaries. (From Hall et al. 1936.)

Vo2 max at an altitude of 3100 m than the two with normal hemoglobin.
Numerical modeling gives some basis for these
findings by showing that the increased oxygen affinity of the hemoglobin improves oxygenation in the
pulmonary capillaries under conditions of diffusion
limitation more than it interferes with the release of
oxygen by peripheral capillaries (Bencowitz et al.
1982). Table 6.1 lists some of the strategies used by
animals (including humans) to increase the oxygen
affinity of their hemoglobin under hypoxic conditions.
Table 6.1 Strategies for increasing oxygen affinity in
chronic hypoxia

Different sequence in
globin chain
Decrease in red cell
2,3-DPG
Decrease in ATP
Different hemoglobin,
small Bohr effect
Mutant hemoglobin
(Andrew-Minneapolis)
Respiratory alkalosis

Human fetus, bar-headed

goose, toadfish
Fetus of dog, horse, pig
Trout, eel
Tadpole
Family in Minnesota
Climber at extreme altitude

Climbers at very high altitude tend to have an

increased arterial blood pH, which causes a leftward
shift of the oxygen dissociation curve. This is caused
by a partially compensated respiratory alkalosis and
was the case for members of the 1981 American
Medical Research Expedition to Everest who spent
several weeks at an altitude of 6300 m. The mean
arterial pH of three subjects was 7.47 (Winslow et al.
1984), which is well above the normal range.
At extreme altitudes, there is evidence of extraordinary degrees of respiratory alkalosis. For example, when Pizzo took alveolar gas samples on the
summit of Mount Everest, there is good evidence
that his arterial pH exceeded 7.7. This value is based
on a measured alveolar PC02 of 7.5 mm Hg, and a
base excess measured in venous blood taken on the
following morning of -5.9 mmol Ir1. This extreme
respiratory alkalosis caused a marked leftward shift
of the oxygen dissociation curve with a calculated in
vivo P50 of about 19 mm Hg. Thus a climber on the
summit of Mount Everest develops conditions rather
similar to those in the human fetus where the arterial
P02 is less than 30 mm Hg and the P50 is less than
20 mm Hg.

6.4 PULMONARY DIFFUSING CAPACITY

AT HIGH ALTITUDE
6.4.1

Acclimatized lowlanders

Barcroft and his colleagues measured the diffusing

capacity for carbon monoxide in five members of
the expedition to Cerro de Pasco in the Peruvian
Andes in 1921-2. They used the single breath
method which had recently been described by
Krogh (1915) and the measurements were made at
rest. There was no consistent change from the sea
level values though the investigators believed that
there was a slight tendency for the diffusing capacity
to rise. They pointed out, however, that this small
change would not be an important element in
acclimatization (Barcroft et al. 1923). Subsequent
investigators have confirmed the absence of change
or found only a very small (less than 10 per cent)
increase in diffusing capacity for carbon monoxide
in resting subjects after periods of up to several
months at altitudes of up to 4560 m (Kreuzer and

Pulmonary diffusing capacity at high altitude 75

altitude and indicated that there was no change in the

diffusion properties of the lung itself after
7-10 weeks of acclimatization at an altitude of
5800m.
Acute mountain sickness (AMS) has been shown
to reduce the diffusing capacity for carbon monoxide
at high altitude (Ge et al. 1997). Presumably the
mechanism is subacute pulmonary edema.
Interestingly, the diffusing capacity was also reduced
following a Himalayan expedition to altitudes of
4900 m and above compared with measurements
made prior to the expedition. The fall in diffusing
capacity was accompanied by small reductions in
maximal cardiac index and V02inax. A possible explanation was the wasting of skeletal muscle which
resulted in a reduced cardiac output and therefore
diffusing capacity.

6.4*2 High altitude natives

Figure 6.7 Diffusing capacities (Dj in ml min~J mm Hg~1
measured at sea level (London), 15 300ft (4700 m) and 19 000ft
(5800 m) in acclimatized lowlanders exercising at:
(a) 300 kgm min~1 and (b) 900 kgm min~1. Note the moderate
increase in diffusing capacity of carbon monoxide with altitude.
(From West 1962.)

van Lookeren Campagne 1965, DeGraff et al 1970,

Guleriaeta/. 1971, Dempsey et al. 1978).
Measurements on exercising subjects at altitudes
up to 5800 m showed that after 7-10 weeks of
acclimatization, there was an increase in pulmonary
diffusing capacity of 15-20 per cent (Figure 6.7).
However, this small change could be wholly
accounted for by the increased rate of reaction of carbon monoxide with hemoglobin due to hypoxia and
by the increased blood hemoglobin concentration
(West 1962a).
The mechanism of this increase can be explained
by reference to Figure 6.2. The 'resistance' attributable to the rate of combination of oxygen with hemoglobin is given by 1/(9VC). It has been found
experimentally that the value of 6 varies depending
on the ambient P02. At low P02 values, 0 is increased
and therefore the resistance to oxygen transfer is
decreased. An additional factor is the increased blood
hemoglobin concentration which, for a given value
of Vc (capillary blood volume), increases the amount
of hemoglobin present. Thus these factors
completely accounted for the small observed increase
in diffusing capacity for carbon monoxide at high

Several studies have shown that people who live permanently at high altitude (high altitude natives or
highlanders) have pulmonary diffusing capacities that
are about 20-50 per cent higher than the predicted values, or than in lowlander controls (Figure 6.8). One of
the first studies was by Velasquez (1956) who studied
12 native residents of Morococha (altitude 4550 m)
and showed that the diffusing capacity for oxygen was
consistently higher than in similar subjects at sea level.
Remmers and Mithoefer (1969) showed that Andean
Indians at an altitude of 3700 m had a diffusing capacity for carbon monoxide which was some 50 per cent
higher than predicted. High diffusing capacities have
also been reported in Caucasians living at an altitude
of 3100m (DeGraff et al. 1970, Dempsey et al. 1978).
The increased diffusing capacities were demonstrated
both during rest and exercise.
A potential problem in such studies is the appropriateness of the predicted values for diffusing capacity. For example, in the study by Remmers and
Mithoefer (1969), predicted values were obtained
from Caucasian North Americans and were applied
to the South American high altitude Indian population. This may introduce errors because of ethnic differences in body build. However, in other studies
such as that by Dempsey et al. (1971), diffusing
capacities were compared between lowlanders and
highlanders in similar ethnic groups (Figure 6.8).
The increased diffusing capacities can presum-

76 Lung diffusion

Figure 6.8 Diffusing capacities for

carbon monoxide as obtained by the
single breath method (a) and steadystate method (b) in three groups of
subjects; lowlanders at 250 m (O and
>), lowlanders sojourning at 3100 m
(9, A and indicate different periods
at this altitude), and native highlanders
at 3100 m. The broken line indicates
the measured data for highlanders; the
continuous line shows the results after
correction for 7/9. All the
measurements are on white people, the
3100 m data being from Leadville,
Colorado. Note the higher diffusing
capacities of the highlanders both at
rest and on exercise. (From Dempsey et
al. 1971.)

ably be explained by the larger lungs which result

in an increased alveolar surface area and capillary
blood volume. Barcroft et al. (1923) commented
on the remarkable chest development of the
Peruvian natives in Cerro de Pasco and these early
investigators made chest radiographs to confirm
this. The radiographs showed that the ratio of
chest width to height was greater in the high altitude natives than in the Anglo-Saxon lowlanders
(expedition members). Children who are raised at
altitudes of 3000 m have been shown to have
increased lung volumes and diffusing capacities (de
Meer et al. 1995). It has been shown experimentally that animals exposed to low oxygen partial
pressures during their active growth phase develop
larger lungs and bigger diffusing capacities than
animals reared in a normoxic environment (Figure
6.9) (Bartlett and Remmers 1971, Burri and Weibel
1971). This appears to be an adequate explanation
for the observed high diffusing capacities, and
would also account for the persistence of an
increased diffusing capacity for carbon monoxide
in highlanders after a prolonged period spent at
sea level as observed by Guleria and his co-workers
(1971). However, Lechner et al (1982) presented
evidence that the lungs only grow faster in a
hypoxic environment and the end result is the
same lung volume as in normoxic animals. The
issue is unresolved.

6.5 DIFFUSION LIMITATION OF OXYGEN

TRANSFER AT HIGH ALTITUDE
The significance of pulmonary diffusion at high altitude is that it may be a limiting factor in oxygen
uptake. A considerable amount of evidence now supports this.
One of the first groups to suggest diffusion limitation of oxygen uptake at altitude was Barcroft and his
colleagues (1923). They concluded from their measurements of pulmonary diffusing capacity for carbon monoxide at an altitude of 4300 m that P02
equilibration between alveolar gas and the blood at
the end of the capillary would not be achieved, especially on exercise. Subsequently Houston and Riley
(1947) measured alveolar-arterial P02 differences in
four subjects who spent 32 days in a low pressure
chamber in which the pressure was gradually
reduced from 760 to 320 mm Hg (Operation Everest
I). Measurements were made during rest and during
relatively low levels of exercise (oxygen uptakes less
than 1200 mL min"1 at simulated high altitude).
During exercise, the alveolar-arterial P0z difference
was increased to about 10 mmHg, which they correctly ascribed to diffusion limitation.
During the Silver Hut Expedition of 1960-1, measurements of arterial oxygen saturation by ear
oximetry were made on five subjects who lived for

Diffusion limitation of oxygen transfer at high altitude 77

Figure 6.9 (a) Increase in lung

volume Vifrom day 23 to day 44 of
life in three groups of rats exposed to
an altitude of 3450 m (]J), sea level
(cross-hatched), and 40 per cent
oxygen at sea level (OC). Note that
lung volume increased most in the
hypoxic and least in the hyperoxic
animals, (b) Pulmonary diffusing
capacity estimated

morphometrically

in the same three groups of animals

at the 44th day. Note that the
diffusing capacities reflected the
changes in lung volume. C shows a
control group. (From Burri and Weibel
1971.)

4 months at an altitude of 5800 m (PB380 mm Hg) in

a prefabricated hut. The average arterial oxygen saturation at rest was 67 per cent and this fell at work levels of 300 and 900 kgm min"1 to 63 per cent and 56
per cent respectively (West et al. 1962). The progressive fall in arterial oxygen saturation as the work level
was raised occurred in the face of an increasing alveolar P02 and was strong evidence for diffusion limitation of oxygen transfer. Alveolar-arterial differences
were calculated and nine measurements at the maximal exercise level gave a mean P02 difference of
26 mm Hg with a standard deviation of 4 mm Hg.
Calculations based on the Bohr integration procedure showed that the results were consistent with a
maximum pulmonary diffusing capacity for oxygen
of about 60 mL min'1 mm Hg"1.
Further evidence for diffusion limitation of oxygen transfer during exercise at very high altitudes

was obtained on the 1981 American Medical

Research Expedition to Everest. Fifteen subjects
spent up to 4 weeks at an altitude of 6300 m (PB
350 mm Hg) and arterial oxygen saturation was
measured by oximeter at rest and during increasing levels of work (Figure 6.10). Again there was
a progressive fall in arterial oxygen saturation
as the work level was increased from rest to
1200 kg min'1, equivalent to an oxygen consumption of about 2.3 L min"1. The calculated alveolar-arterial P02 difference at this highest work
level was 21 mm Hg (West et al. 1983c).
Figure 6.10 also shows that additional measurements were made with subjects breathing 16 per cent
and 14 per cent oxygen at this very high altitude. The
latter gave an inspired P02 of 42 mm Hg, equivalent
to that encountered by a climber breathing air on the
summit of Mount Everest. Note the very abrupt fall

78 Lung diffusion

Figure 6.10 Arterial oxygen saturation as measured by ear

oximetry plotted against work rate at sea level and 6300m

Figure 6.11 Relationship between the degree of

altitude. The two lower lines were obtained with subjects

ventilation/perfusion inequality in the lung and oxygen uptake in

breathing 16 per cent and 14 per cent oxygen at 6300m. (From

subjects during a simulated ascent of Mount Everest in a low

Mfesfetal. 1983c.)

pressure chamber (Operation Everest II). The ordinate shows the

log SD of blood flow which is a measure of ventilation/perfusion

in arterial oxygen saturation as work rate was

increased at this highest altitude on Earth. Two subjects performed maximum exercise while breathing
14 per cent oxygen and in one of them the oximeter
reading fell to less than 10 per cent oxygen saturation
at one point during the experiment! Although the
calibration of the oximeter at such values is unreliable, the actual saturation must have been extremely
low.
A possible criticism of the measurements
described so far is that no account was taken ofventilation/perfusion inequalities within the lung, and
these may have contributed to the observed fall in
arterial oxygen saturation and the increased
alveolar-arterial P02 difference. Allowance for this
possible factor can only be made if there is an independent measurement of ventilation/perfusion
inequality. This was done by Wagner and his colleagues, both in an acute low pressure chamber
study, and in a 40-day simulated ascent of Mount
Everest (Operation Everest II). These studies are
important because they show that some increase in
ventilation/perfusion inequality occurred at rest and
on exercise both during acute exposure to low pressure and in subjects acclimatized to high altitude for
periods up to 40 days. The measurements of ventilation/perfusion inequality were made using the multi-

inequality. Note that both a reduction of barometric pressure (P&

measured in mm Hg) and increase in work rate tended to increase
the degree of ventilation/perfusion inequality. (From Wagner et al.
1987.)

pie inert gas elimination technique (Wagner et al.

1974). Inert gas exchange is not diffusion limited,
even during maximal exercise.
Figure 6.11 shows the increase in ventilation/perfusion inequality caused both by increasing altitude
and increasing work level in the 40-day low pressure
chamber experiment (Wagner et al. 1987). The vertical scale shows the mean log standard deviation of
the blood flow distribution which is one measure of
ventilation/perfusion inequality. It can be seen that
this index was about 0.5 during rest at sea level but
increased slightly when the oxygen consumption was
raised to over 3 L min"1 during exercise at sea level.
At very high altitude, where the barometric pressure
was 347 mm Hg, the resting standard deviation rose
to approximately 0.9 and it increased further to over
1.5 with exercise. The explanation of these intriguing
data is uncertain but may be subclinical pulmonary
edema. There was evidence that rapid ascent was
more likely to result in ventilation/perfusion
inequality than slow ascent, suggesting that inadequate acclimatization may have been an important
factor.

Diffusion limitation of oxygen transfer at high altitude 79

Figure 6.12 Relationship between alveolar-arterial ?02 difference

and the oxygen uptake in Operation Everest II (compare Figure
6.11). The predicted difference refers to that calculated from the
measured amount of ventilation/perfusion

inequality. Note that,

at the highest altitudes, the measured differences considerably

exceeded the predicted values, indicating diffusion limitation of
oxygen uptake. For the measurements at 240 mm Hg, the subjects
breathed an oxygen mixture to give an inspired P02 of 43 mm Hg.
(From Wagner et a I. 1987.)

Using these independent measurements of the

amount of ventilation/perfusion inequality present,
it was possible to separate the contribution of diffusion limitation and ventilation/perfusion inequality
to the observed increase of the alveolar-arterial P02
difference at high altitude. The results are shown in
Figure 6.12. The arterial P02 was directly measured
on arterial samples. It can be seen that the measured alveolar-arterial P02 difference increased to a
mean of about 13 mm Hg during maximal exercise
at a barometric pressure of 347 mm Hg where the
oxygen consumption was a little over 2 L mur1. At
higher simulated altitudes, the maximum alveolararterial P02 differences were smaller. This can be
explained by the smaller maximum oxygen uptakes,
and the fact that the subjects were operating on the
lower, steeper region of the oxygen dissociation
curve.
Also shown in Figure 6.12 are the predicted
alveolar-arterial P02 differences for the degree of
ventilation/perfusion inequality measured at the
same time by means of the multiple inert gas elimination technique. These predicted P02 differences
decreased as the altitude increased despite the
broadening of the distributions of ventilation/perfusion ratios as shown in Figure 6.11. Again, the
reason is that the P02 values are lower on the
curvilinear oxygen dissociation curve. The data
allow the total alveolar-arterial P02 difference to be
divided into two components, one caused by ventilation/perfusion inequality, and the rest presumably
attributable to diffusion limitation. The results
show that, at sea level, essentially all of the alveolar-arterial P02 difference was attributable to
ventilation/perfusion inequality up to an oxygen
consumption of nearly 3 L min~'. Above that high
exercise level, some diffusion limitation apparently
occurred. By contrast, at a barometric pressure of
429 mm Hg, the measured alveolar-arterial P02 difference exceeded that predicted from the amount of
ventilation/perfusion inequality when the oxygen
uptake was above about 1 L min-1. This was also
true at a barometric pressure of 347 mm Hg. At the
higher simulated altitudes, with barometric pressures of 282 and 240 mmHg, almost all of the
observed alveolar-arterial P02 difference during
exercise could be ascribed to diffusion limitation.
These elegant studies go a long way towards elucidating the role of diffusion in the hypoxemia of
high altitude during exercise.

80 Lung diffusion

6.6 DIFFUSION IN THE PLACENTA AT

HIGH ALTITUDE

The fetus derives its oxygen via the placenta rather

than the lung. Gas exchange in the placenta is much
less efficient than in the lung and, for example, the
P02 in the descending aorta of the human fetus is less
than 25 mmHg. The fetus must be even more
hypoxic at high altitude and it is known that birth
weight is reduced at high altitude, and that smaller
birth weights at high altitude are associated with
increased infant morbidity and mortality (Lichty et
al 1957, Moore etal. 1998a).
An interesting question is whether the diffusion
properties of the placenta are improved at high altitude, just as the diffusing capacity in high altitude

natives is apparently raised. There is some evidence

for this. Reshetnikova et al. (1994) examined 10 normal term placentas from women in Kirghizstan up to
altitudes of 2800 m and found that there was an
increase in capillary volume, and that the harmonic
mean thickness of the maternal-fetal barrier fell
from 6.9 fim in controls to 4.8 |lm at high altitude.
They calculated that the morphometric diffusing
capacity of the villous membrane for oxygen was significantly increased, by about 80 per cent. However,
Mayhew (1991) found somewhat different results in
placentas from populations living at 3600 m compared with 400 m altitude in Bolivia. Although there
was some improvement in diffusion properties on
the maternal side of the placenta, these did not
extend to the fetal side. Other research on this
important topic is continuing.

7
Cardiovascular system
7.1
7.2
7.3

Introduction
Historical
Cardiac function

81
81
82

7.4
7.5

Systemic blood pressure

Pulmonary circulation

89
89

SUMMARY

7.1

Important changes in the cardiovascular system

occur at high altitude. Cardiac output increases
following acute exposure to high altitude, but in
acclimatized lowlanders and high altitude natives, the
cardiac output for a given work rate is the same as at
sea level. Nevertheless, because of the polycythemia,
hemoglobin flow is increased. Heart rate for a given
work rate is higher than at sea level, with the result
that stroke volume is reduced at high altitude.
However, this is not caused by a reduced myocardial
contractility; on the contrary, this is preserved up to
very high altitudes in normal subjects. Abnormal
heart rhythms, such as premature ventricular or
atrial contractions, are unusual despite the severe
hypoxemia. However, sinus arrhythmia accompanying periodic breathing is very common at high
altitude. Changes in systemic blood pressure are small
and variable; some studies report a reduction in
hypertension when lowlanders move to high altitude.
Pulmonary hypertension is striking at high altitude,
in both newcomers and high altitude natives, particularly on exercise. There is some evidence that Tibetans
have smaller degrees of pulmonary hypertension than
other highlanders. The hypertension is relieved by
oxygen breathing when the exposure to high altitude
is acute, but after a few days the response to oxygen is
less, apparently because of vascular remodeling. Right
ventricular hypertrophy and corresponding electrocardiographic changes are seen.

The cardiovascular system is an essential link in the

process of transporting oxygen from the air to the
mitochondria, and it therefore has an important
role in acclimatization and adaptation to the
oxygen-depleted environment of high altitude.
However, aspects of the cardiovascular system at
high altitude have not been as extensively studied
as their importance may suggest. The chief reason
for this is the difficulties of measurement, especially
the invasive investigations necessary reliably to
measure cardiac output and pulmonary artery
pressure.
In this chapter we look at available data on many
aspects of the cardiovascular system, though, as will
be seen, there are still many areas of ignorance. This
chapter is closely related to some others. The cerebral
circulation is discussed in Chapter 16, and changes in
the capillary circulation in high altitude acclimatization and adaptation are considered in Chapter 10.
High altitude pulmonary edema and high altitude
cerebral edema are discussed in Chapters 19 and 20
respectively.

7.2

INTRODUCTION

HISTORICAL

Early travelers to high altitudes frequently complained of symptoms related to the cardiovascular

82 Cardiovascular system

system. Many of these accounts were collected by

Paul Bert and set out in the first chapter of his
classical book La Pression Barometrique (Bert 1878,
p. 29 in the 1943 translation). For example, he
quotes the great explorer Alexander von
Humboldt at an altitude of 2773 'fathoms' (about
5070 m) on Chimborazo in the South American
Andes complaining that 'blood issued from our
lips and eyes'. Many other travelers gave accounts
of bleeding from the mouth, eyes and nostrils, and
they often attributed this to the low barometric
pressure which, they argued, did not balance the
pressures within the blood vessels. Of course this
is fallacious reasoning because all vascular
pressures fall along with the ambient atmospheric
pressure (section 2.1). These early reports of
bleeding are intriguing because this is not a
typical feature of mountain sickness as we see it
today.
Another common complaint of these early
mountain travelers was cardiac palpitations,
especially on exercise. Typical is the passage quoted
by Bert (Bert 1878, p. 37 in 1943 translation) from
the explorer D'Orbigny who stated when he was on
the crest of the Cordilleras that 'at the least movement, I felt violent palpitations'. The most observant
travelers measured their pulse rate and noted that
mild exercise such as riding caused it to increase
dramatically although it was normal at rest. Cloves of
garlic were frequently eaten to relieve these
symptoms, which often seem exaggerated to the
modern reader.
An interesting historical vignette was the occurrence of edema in cattle while grazing at high
altitude in Utah and Colorado early in the twentieth
century (Hecht et al. 1962). The condition is known
as brisket disease because the edema is most
prominent in that part of the animal between the
forelegs and neck (brisket). The condition is caused
by right heart failure as a result of severe pulmonary
hypertension caused, at least in part, by hypoxic
pulmonary vasoconstriction.
Early climbers on Mount Everest who became
fatigued were sometimes diagnosed as having
'dilatation' of the heart. This was thought to be one
of the signs of failure to acclimatize. As late as 1934,
Leonard Hill stated that 'degeneration of the heart
and other organs due to low oxygen pressure in the
tissues, is a chief danger which the Everest climbers
have to face'(Hill 1934).

73

73.1

CARDIAC FUNCTION

Cardiac output

It is generally accepted that acute hypoxia causes an

increase in cardiac output both at rest and for a given
level of exercise compared with normoxia. These
responses are seen at sea level following inhalation of
low oxygen mixtures, and on acute exposure to high
altitude (Asmussen and Consolazio 1941, Keys et al.
1943, Honig and Tenney 1957, Kontos et al. 1967,
Vogel and Harris 1967). There is also good evidence
that, in well acclimatized lowlanders at high altitude,
the relationship between cardiac output and work
rate returns to the sea level value (Pugh 1964c,
Reeves et al. 1987). On the other hand, there is some
uncertainty about the changes following short
periods of acclimatization.
Perhaps the first systematic studies of cardiac
output at high altitude were made by Douglas,
Haldane and their colleagues (1913) on the AngloAmerican Pikes Peak Expedition where they made
measurements on themselves by means of ballistocardiography. No consistent changes in stroke
volume of the heart were noted. They therefore concluded that cardiac output at rest was proportional to
heart rate, which they showed increased over the first
11 days at 4300 m and subsequently decreased
towards normal. Barcroft and his colleagues (1923)
used an indirect Pick technique to measure cardiac
output in their study of themselves at Cerro de Pasco
in the Peruvian Andes at an altitude of 4330 m. They
reported essentially no difference in acclimatized
subjects compared with sea level.
Grollman (1930) made an impressive series of
measurements on Pikes Peak in 1929 using the
acetylene rebreathing method. He reported that the
cardiac output increased soon after reaching high
altitude, with a maximum value approximately
5 days later. However, by day 12 it had returned to its
sea level value. Similar changes were found by
Christensen and Forbes (1937) during the
International High Altitude Expedition to Chile.
Most recent investigators have reported similar
findings. Figure 7.1 shows the increase in cardiac
output during the first 40 h of acute exposure to
simulated high altitude (Vogel and Harris 1967).
Klausen (1966) showed an increase in cardiac output
following ascent to an altitude of 3800 m but after

Cardiac function 83

Figure 7.1 Cardiac output (solid line),

mean systemic arterial pressure (dashed
line), and calculated peripheral resistance
(dotted line) during acute exposure to
simulated altitude of 2000 ft (610 m),
11000ft (3353 m) and 15 000ft
(4572 m). Measurements were made on
16 subjects after 10, 20, 30 and 40 h at
each altitude. The results from the
different altitude exposures were pooled.
Mean SE indicated by vertical bars
(1 dyne = 10~5 N). (From Vogel and Harris
1967.)

Figure 7.2 Cardiac output in

relation to work rate and related
variables as obtained from four well
acclimatized subjects during the
Himalayan Scientific and
Mountaineering Expedition. Note
that the cardiac output/work rate
relationship is the same at an
altitude of 5800 m (x, barometric
pressure 380 mm Hg) as at sea level
(J. (From Pugh 1964a.)

84 Cardiovascular system

3-4 weeks it had returned to its sea level value.

Similar findings were reported by Vogel and his
colleagues (1967) on Pikes Peak at an altitude of
4300 m. However, Alexander et al. (1967) reported a
decrease in cardiac output during exercise after
10 days at 3100 m compared with sea level. The
decrease was caused by a fall in stroke volume.
In well acclimatized lowlanders at high altitude,
and in high altitude natives, cardiac output in
relation to work level is the same as at sea level. This
was shown by Pugh (1964c) during the Silver Hut
Expedition at an altitude of 5800 m where the
measurements were made by acetylene rebreathing
(Figure 7.2). Further measurements were made by
Cerretelli (1976a) at the Everest Base Camp where
the subjects had acclimatized for 2-3 months. Reeves
et al. (1987) reported the same finding on subjects
during Operation Everest II where a remarkable
series of measurements was made down to an
inspired P02 of 43 mm Hg, equivalent to that of the
Everest summit (Figure 7.3).

High altitude natives also show the same relationship between cardiac output and oxygen consumption during exercise as at sea level. Vogel et al.
(1974) studied eight natives of Cerro de Pasco, Peru,
at an altitude of 4350 m and again after 8-13 days at
Lima (sea level) and showed that the results were
almost superimposable (Figure 7.4).

Figure 7.4 Cardiac index (0) against oxygen uptake (V02) (both
related to body surface area) in high altitude natives at 4350 m
(H) and again after 8-13 days at sea level ( ). (From Vogel et al.
1974.)

Figure 7.3 Cardiac output (by thermodilution) and stroke volume

plotted against oxygen uptake (V02) and heart rate at barometric
pressures of 760 (9,
240 (A,

= 8), 347 (O, n = 6), 282 (A, n = 4) and

= 2) mm Hg during Operation Everest II. For the

measurements at 240 mm Hg, the subjects breathed an oxygen

mixture to give an inspired P02 of 43 mm Hg. (From Reeves et al.
1987.)

It is perhaps surprising that cardiac output in well

acclimatized lowlanders and high altitude natives
bears the same relationship to work rate (or power)
as it does at sea level. After all, there is plenty of
evidence of severe tissue hypoxia during exercise at
high altitude, and at first sight it seems that one way
of increasing the tissue P02 would be to raise cardiac
output and thus peripheral oxygen delivery. However, in a theoretical study, Wagner (1996) has
shown that although increasing cardiac output
improves calculated maximal oxygen consumption

Cardiac function 85

at sea level, the improvement becomes progressively

less as altitude increases. In fact, calculations done
for a subject on the summit of Mount Everest show
that Vo2 max was essentially unchanged as cardiac output was increased from 50 per cent to 150 per cent of
its expected value (Figure 7.5).

availability. At medium altitudes, the calculated

improvement in V0 max that accompanies an increase
in cardiac output or hemoglobin concentration is
intermediate between the values at sea level and
extreme altitude.
Although cardiac output in relation to work level
is unchanged in acclimatized subjects at high
altitude, and in high altitude natives, hemoglobin
flow is appreciably increased because of the polycythemia. As long ago as 1930, Grollman suggested
that the return of cardiac output to its sea level value
was related in some way to the increase in hemoglobin concentration of the blood.

73,2

Figure 7.5 Theoretical study of the effects of changing cardiac

output on maximal oxygen consumption (V02maJ at sea level and
at extreme altitude. Note that although V02max improves at sea
level, there is essentially no change at extreme altitude. This is
explained by diffusion limitation in the lung and tissues. (From
Wagner 1996.)

A very similar picture emerged when hemoglobin

concentration was varied between 50 per cent and
150 per cent of its expected value. Note that in the
case of both cardiac output and hemoglobin concentration, calculated oxygen delivery to the tissues was
greatly increased. The reason for the lack of improvement in Vo2max with increases in cardiac output and
hemoglobin concentration (and therefore oxygen
delivery) is that diffusion impairment of oxygen,
both in the lungs and in the muscles, reduces its

Heart rate

Acute hypoxia causes an increase in heart rate both at

rest and for a given level of exercise, just as is the case
for cardiac output. The higher the altitude, the
greater the increase in heart rate. At simulated
altitudes of 4000-4600 m where acute exposure
depresses the arterial P02 to 40-45 mm Hg, resting
heart rates increase by 40-50 per cent above the sea
level values (Kontos et al. 1967, Vogel and Harris
1967).
In acclimatized subjects at high altitude, resting
heart rates return to approximately the sea level value
up to an altitude of about 4500 m, though there is
some individual variation (Rotta et al. 1956,
Penaloza et al. 1963). On exercise, heart rate for a
given work rate or oxygen consumption exceeds the
sea level value. Figure 7.6 shows comparisons of
heart rate at sea level and at an altitude of 5800 m in
four subjects from the Himalayan Scientific and
Mountaineering Expedition who were well acclimatized to that altitude (Pugh
It can be seen that
the sea level values were generally lower than the high
altitude measurements. However, in three of the four
subjects the data points crossed at the highest work
level that was tolerated at the high altitude. Note that,
in every instance, this crossover was associated with a
reduction in measured oxygen consumption, suggesting that at the high work rate, an increasing
amount of work was being accomplished anaerobically.
Maximal heart rate, that is the heart rate at
maximal exercise, is reduced in acclimatized subjects
at high altitude. This is clearly seen from Figure 7.6.
In Operation Everest II, maximal heart rates

86 Cardiovascular system

Figure 7.6 Heart rate (HR,

), cardiac

output (CO, ), and oxygen uptake (V02,

) against work rate in four well
acclimatized subjects at an altitude of
5800 m. Measurements taken at sea level ( )
and 5800 m (O, PB 380 mm Hg). (From Pugh
1964a.)

decreased from 160 7 at sea level to 137 4 at a

simulated altitude of 6100 m, 123 6 at 7620 m and
118 3 at 8848 m (Reeves et al. 1987). For a given
work level, heart rates were greater at high altitude
compared with sea level, though, interestingly, there
seemed to be little difference between the measurements made at barometric pressures of 347, 282 and
240 mm Hg, as shown in Figure 7.7. This is possibly a
reflection of the limited degree of acclimatization of
the subjects at the higher altitudes (West 1988a).
Richalet (1990) has argued that the reduction of
maximal heart rate in acclimatized subjects at high
altitude represents a physiological adaptation which
reduces cardiac work under conditions of limited
oxygen availability. There is good evidence that
hypoxia induces downregulation of [3-adrenergic
receptors in animal hearts (Voelkel et al. 1981,
Kacimi et al 1992). The role of the autonomic

nervous system in controlling heart rate and cardiac

output is well established. Short periods of exposure
to hypoxia increase the plasma concentration of
epinephrine and norepinephrine (Richalet 1990) and
the increase in heart rate caused by hypoxia is
abolished by beta-blockers (Kontos and Lower
1963).
However, the reduction of maximal heart rate in
acclimatized subjects at high altitude can be interpreted differently. Since heart rate is actually
increased both at rest and at a given work level
compared with sea level (except perhaps at the
highest work level; Figure 7.6), it seems reasonable to
regard the reduced maximal heart rate simply as a
reflection of the reduced maximal work level. For
example, it does not seem reasonable that a climber
on the summit of Mount Everest where the Vo2max is
only 1 L min~' should have a maximal heart rate as

Cardiac function 87

Figure 7.7 Regression lines for heart rate on oxygen uptake at

barometric pressures of 760, 347,282, and 240 mm Hg during
Operation Everest II. For the measurements at 240 mm Hg, the
subjects breathed an oxygen mixture to give an inspired P02 of
43 mm Hg. (From Reeves et a I. 1987.)

high as the same person at sea level when the V02 max
is 4-5 L min'1.
Oxygen breathing in acclimatized subjects at high
altitude reduces the heart rate for a given work level
(Pugh et al. 1964). This is shown in Figure 11.4 where
it can be seen that the heart rate for a given work level
was actually lower than the corresponding measurements at sea level. Possible explanations include the
fact that the arterial P02 at this altitude of 5800 m
with 100 per cent oxygen breathing is higher than at
sea level, and the fact that these subjects had much
higher hemoglobin levels than at sea level because of
the high altitude polycythemia. It is known that heart
rate for a given work rate at sea level is inversely
related to hemoglobin concentration (Richardson
and Guyton 1959).

733

Stroke volume

Since stroke volume is determined by cardiac output

divided by heart rate, its changes at high altitude can
be deduced from those variables described in the last
two sections.
Acute hypoxia causes approximately the same
increase in cardiac output as in heart rate. The result
is no consistent change in stroke volume. This is true
for both rest and exercise (Vogel and Harris 1967).

After a few weeks' exposure to high altitude, the

cardiac output response to work rate is the same as at
sea level (Figures 7.2 and 7.3) but heart rate remains
high (Figures 7.6 and 7.7). This means that stroke
volume is reduced. The fall in stroke volume has
been attributed to depression of myocardial function
as a result of myocardial hypoxia (Alexander et al.
1967) but, as the next section shows, myocardial
contractility is apparently well maintained up to
extremely high altitudes. The reduction of stroke
volume was also confirmed in Operation Everest II
where it was shown that oxygen breathing did not
increase stroke volume for a given pulmonary wedge
or filling pressure. This suggested that the decline in
stroke volume was not caused by severe hypoxic
depression of contractility (Reeves et al. 1987). A
possible contributing factor is a fall in plasma
volume.
Studies of high altitude natives at an altitude of
4350 m gave results similar to those found in
acclimatized lowlanders. Cardiac output against
oxygen consumption at high altitude was almost
identical to the sea level measurements (Figure 7.4),
whereas heart rate was higher at high altitude and
stroke volume was up to 13 per cent less (Vogel et al.
1974).

73.4

Myocardial contractility

As indicated above, stroke volume is reduced at high

altitude both in acclimatized lowlanders and in high
altitude natives compared with sea level. The reduced
stroke volume could be caused by either reduced
cardiac filling or impaired myocardial contractility.
A fall in filling pressures could result from either an
increased heart rate or a reduction of circulating
blood volume, or both.
During Operation Everest II, it was possible to
measure both right atrial mean pressure (filling
pressure for the right ventricle) and pulmonary
wedge pressure (as an index of the filling pressure of
the left ventricle). Both these measurements tended
to fall as simulated altitude increased (Reeves et al.
1987). It was interesting that the right atrial pressures
tended to be low despite pulmonary hypertension
(section 7.5). In general the relationship between
stroke volume and right atrial pressure was
maintained. This finding suggests maintenance of
contractile function. In addition, as indicated above,

88 Cardiovascular system

oxygen breathing did not increase stroke volume for

a given filling pressure, suggesting that the reduced
stroke volume was not caused by hypoxic depression
of contractility.
Additional evidence to support the finding of
normal myocardial contractility came from a twodimensional echocardiography study during
Operation Everest II (Suarez et al. 1987). It was
found that the ventricular ejection fraction, the ratio
of peak systolic pressure to end-systolic volume, and
mean normalized systolic volume at rest were all
sustained at a barometric pressure of 282 mm Hg,
corresponding to an altitude of about 8000 m.
Indeed the surprising observation was made that
during exercise at the level of 60 W, the ejection
fraction was actually higher (79 per cent 2 compared with 69 per cent 8) at a barometric pressure
of 282 mm Hg compared with sea level. The conclusion was that, despite the decreased cardiac
volumes, the severe hypoxemia and the pulmonary
hypertension, cardiac contractile function appeared
to be well maintained.

73.5

Abnormal rhythm

Abnormal rhythms (apart from sinus arrhythmia

during periodic breathing) are uncommon at high
altitude and perhaps this is surprising in view of the
very severe arterial hypoxemia. A resting climber on
the summit of Mount Everest has an arterial P02 of
less than 30 mm Hg (West et al. 1983b, Sutton et al.
1988). During exercise, the arterial P02 falls, principally because of diffusion limitation across the
blood-gas barrier in the lung (West et al. 1983b).
Thus the myocardium is exposed to extremely low
oxygen levels and it is known that the hypoxic
myocardium is prone to rhythm abnormalities
(Josephson and Wellens 1984).
In an electrocardiographic study of 19 subjects
during the 1981 American Medical Research
Expedition to Everest, only one subject had
premature ventricular contractions and these were
recorded at an altitude of 5300 m. Another climber
showed premature atrial contractions at 6300 m
(Karliner et al. 1985). One subject on the 1960-1
Himalayan
Scientific
and
Mountaineering
Expedition showed premature ventricular contractions after exercise at an altitude of 5800 m
(Figure 7.8). However, no other member of the

Figure 7.8 Electrocardiogram showing premature ventricular

contractions occurring after exercise at 5800 m. (From Milledge
1963.)

expedition showed any dysrhythmia (Milledge

1963). Occasional premature ventricular contractions and premature atrial contractions have
been observed by others (Cummings and Lysgaard
1981). Thus it appears that extreme hypoxia of the
otherwise normal myocardium causes little
abnormal rhythm, even at the most extreme altitudes. This conclusion is consistent with the maintenance of normal myocardial contractility even
during the extreme hypoxia of very great altitudes
(Reeves etal. 1987), as discussed in section 7.3.4.
Sinus arrhythmia accompanying the periodic
breathing of sleep is extremely common at high
altitude (Chapter 13). Indeed, the periodic slowing
of the heart can be reliably used to identify the
presence of periodic breathing at sea level
(Guilleminault et al. 1984) and was used in this way
with a Holter monitor to detect periodic breathing in
climbers at an altitude of 8050 m during the
American Medical Research Expedition to Everest
(West et al. 1986). It is likely that the most extreme
arterial hypoxemia for a given altitude occurs during
the periodic breathing of sleep following the periods
of apnea. It is not surprising that occasional
premature ventricular and premature atrial contractions are then sometimes seen. For example,
during the four sleep studies at 8050 m, one individual had occasional premature ventricular contractions, another had atrial bigeminy and a third
had occasional premature atrial beats (Karliner et al.
1985).

73.6

Coronary circulation

The myocardium normally extracts a large

proportion of the oxygen from the coronary arterial

Pulmonary circulation 89

blood, with the result that the venous P02 has one of
the lowest values of all organs in the body. It is
perhaps surprising therefore that coronary blood
flow has been shown to be reduced in permanent
residents of high altitude compared with people at
sea level. Moret (1971) measured coronary flow in
two groups of people at La Paz (3700 m) and Cerro
de Pasco (4375 m) and compared them with a group
at sea level. The flow per 100 g of left ventricle was
some 30 per cent less in the high altitude natives. A
reduction of coronary blood flow in lowlanders
following ascent to high altitude was found by
Grovereta/. (1970).
Despite this, there appears to be little evidence of
myocardial ischemia in people living at high altitude
(Arias-Stella and Topilsky 1971). These authors
showed that casts of the coronary vessels had a
greater density of peripheral ramifications than those
of sea level controls. This might be part of the explanation for the apparent low incidence of angina and
other features of myocardial ischemia.

7A

SYSTEMIC BLOOD PRESSURE

Acute hypoxia causes essentially no change in the

mean systemic arterial blood pressure in humans, at
least up to altitudes of 4600 m (Kontos et al 1967,
Vogel and Harris 1967). This is in contrast to the
dog, in which acute hypoxia results in a rise of mean
arterial pressure (Kontos etal. 1967). Some measurements show that acclimatized lowlanders develop a
rise in diastolic pressure with a corresponding
decrease in pulse pressure (Brendel 1956). However,
other studies suggest that the systemic blood
pressure is lower in lowlanders living at high altitude
than in sea level residents (Rotta et al. 1956,
Marticorena et al. 1969, Penaloza 1971). In one
study, it was shown that a stay of 1 year at an altitude
of 4500 m resulted in a decrease of systemic systolic
and diastolic pressures (Rotta et al. 1956). In another
study it was found that some patients with systemic
hypertension who moved to an altitude of 3750 m
had a reduction in their level of systemic blood
pressure (Penaloza 1971). A study of the prevalence
of systemic hypertension at altitudes of 4100-4360 m
in Peru, compared with two communities at sea
level, showed a prevalence of hypertension in men at
least 12 times greater at sea level than at high altitude

(Ruiz and Penaloza 1977). The difference was even

more marked in women.
In high altitude natives living at 4350 m, Vogel et
al. (1974) found that the mean brachial arterial blood
pressure was consistently higher during exercise than
in the same subjects at sea level. The increase in mean
systemic arterial pressure which occurs during the
course of heavy exercise is apparently the same in
acclimatized lowlanders as it is in sea level residents.

7.5
7.5.1

PULMONARY CIRCULATION
Pulmonary hypertension

One of the most striking cardiovascular changes at

high altitude is the occurrence of pulmonary hypertension caused by an increase in pulmonary vascular
resistance. This is seen in subjects exposed to acute
hypoxia, in acclimatized lowlanders at high altitude
and in most high altitude natives. The pulmonary
hypertension of acute hypoxia is alleviated by oxygen
breathing, but this is not the case in acclimatized
lowlanders or high altitude natives. In normal
subjects at sea level who are given low oxygen
mixtures to breathe, mean pulmonary artery pressure almost always increases. In early studies, Motley
etal. (1947) reported an increase of 13-23 mm Hg as
a result of breathing 10 per cent oxygen in nitrogen
for 10 min. This study followed the initial demonstration by von Euler and Liljestrand (1946) that the
pulmonary arterial pressure in the cat increased
when the animals breathed 10 per cent oxygen in
nitrogen. The increase in pulmonary vascular resistance is caused by vasoconstriction, probably mainly
as a result of contraction of smooth muscle in small
pulmonary arteries.
Extensive studies of the effects of acute hypoxia on
the pulmonary circulation have been made in
humans and in a variety of animals. Figure 7.9 shows
a typical study by Barer et al. (1970) in anesthetized
cats in which the left lower lobe of the lung was made
hypoxic and its blood flow was plotted against the
alveolar P0r Note the typical nonlinear stimulusresponse curve. When the alveolar P02 was altered in
the region above 100 mm Hg, little change in blood
flow and therefore vascular resistance was seen.
However, when the alveolar P02 was reduced to
approximately 70 mm Hg, obvious vasoconstriction

90 Cardiovascular system

Figure 7.9 Blood flow from left lower lobe of

open-chest anesthetized cats against ?02 of the
pulmonary venous blood from the lobe. The
lobe was ventilated with different inspired gas
mixtures while the rest of the lung was
breathing air (O) or 100 per cent oxygen (%).
(From Barer et al. 1970.)

occurred, and at very low P02 values approaching

those of mixed venous blood, the local blood flow
was almost abolished.
There are differences among species in the
stimulus-response curves. In humans, the vasoconstrictor response to acute hypoxia shows considerable variation between individuals, leading Read and
Fowler (1964) to refer to 'responders' and 'nonresponders'. Indeed, some people believe that the
phenomenon of hypoxic pulmonary vasoconstriction is vestigial in the adult and that its most
important function occurs in neonatal life. Here
there is a release of pulmonary vasoconstriction
when the newborn baby starts to breathe air, and the
circulation transforms from the fetal placental mode
to the adult lung mode. Presumably this is where the
primary evolutionary pressure for the phenomenon
comes from.

Acclimatized lowlanders show pulmonary hypertension with a mean pulmonary arterial pressure
increasing from its sea level value of about 12 mm Hg
to about 18 mm Hg after 1 year at 4540 m (Rotta et
al. 1956, Sime et al. 1974). This resting pulmonary
arterial pressure increases considerably during
exercise. Figure 7.10 shows the relationship between
mean pulmonary vascular pressure gradient across
the lung (mean pulmonary arterial pressure minus
pulmonary wedge pressure) and cardiac output in
the subjects of Operation Everest II (Groves et al
1987). Note that the resting values of the gradient
(determined primarily by the mean pulmonary
artery pressure) increased, but the most dramatic
change was in the slope of the pressure gradient with
respect to cardiac output. This indicates the very
striking increase in pulmonary vascular resistance at
these great simulated altitudes.

Figure 7.10 Mean pulmonary artery

pressure (PAM) minus mean pulmonary wedge
pressure (PAWM) plotted against cardiac output
(by thermodilution) at various barometric
pressures (PB) during Operation Everest II. For
the measurements at 240 mm Hg, the subjects
breathed an oxygen mixture to give an
Inspired P02 of 43 mm Hg; , 282 mm Hg; O,
240 mm Hg. (From Groves et al. 1987.)

Pulmonary circulation 91

Figure 7.11 Change in mean pulmonary artery

pressure during alveolar hypoxia in five Tibetans
compared with high altitude residents of North
and South America. (From Groves et al. 1993.)

High altitude natives also show a substantial

increase in mean pulmonary artery pressure during
exercise. In one study, mean pulmonary artery
pressure increased from 26 to 60 mmHg during
exercise at an altitude of 4500 m (Sime et al. 1974).
This was a greater increase than that found in
acclimatized lowlanders.
In contrast to the dramatic effect of oxygen
breathing in acute hypoxia, which causes pulmonary
vascular resistance to return to its pre-hypoxic level,
oxygen breathing has relatively little effect in
acclimatized lowlanders and high altitude natives.
For example, in Operation Everest II, 100 per cent
oxygen breathing was shown to lower cardiac output
and pulmonary artery pressure but there was no
significant fall in pulmonary vascular resistance
(Groves et al 1987). In interpreting this result it
should be recognized that a fall in cardiac output
normally results in an increase in pulmonary vascular
resistance because the reduction in capillary pressure
causes derecruitment of capillaries and a reduction
in caliber of those which remain open (Glazier et al.
1969). Thus the fact that pulmonary vascular resistance did not change when it was expected to rise
indicated that oxygen breathing probably reduced
vascular resistance to some extent. Nevertheless, it is
remarkable that the subjects who were hypoxic for
only 2-3 weeks when the measurements were made
had a substantial degree of irreversibility of the
increased pulmonary vascular resistance. This
implies that there were structural changes in the
pulmonary blood vessels, in addition to simple contraction of vascular smooth muscle, and is consistent
with more recent studies on rapid remodeling of the
pulmonary circulation (Tozzi et al. 1989).

High altitude natives also show little response of

their increased pulmonary vascular resistance to
100 per cent breathing. In this case it is known that
there are substantial structural changes in the lungs
including a large increase in smooth muscle in the
small pulmonary arteries (section 7.5.2).
A study of a small sample of Tibetans suggested
that they may have an unusually small degree of
hypoxic pulmonary vasoconstriction compared with
other high altitude natives (Groves et al. 1993). Five
normal male residents of Lhasa (3658 m) were
studied at rest and during near-maximal ergometer
exercise. The resting mean pulmonary arterial
pressure and pulmonary vascular resistance were
within normal values for sea level. Alveolar hypoxia
resulted in a smaller rise of mean pulmonary artery
pressure than in other high altitude residents of
North and South America (Reeves and Grover 1975)
(Figure 7.11). Exercise increased cardiac output
more than threefold but did not elevate pulmonary
vascular resistance; 100 per cent oxygen breathing
during exercise did not reduce pulmonary arterial
pressure or vascular resistance. The authors argued
that elevated pulmonary arterial pressure in high
altitude residents may be a maladaptive response to
chronic hypoxia, and the findings indicated
improved adaptation in a group that has been at high
altitude for a very long period.
7.5*2 Mechanisms and structural
changes
In acute hypoxia, the mechanism of hypoxic
pulmonary vasoconstriction remains obscure despite
a great deal of research. Since the phenomenon

92 Cardiovascular system

occurs in excised isolated lungs, it clearly does not

depend on central nervous connections. Furthermore, excised segments of pulmonary artery can be
shown to constrict if their environment is made
hypoxic (Lloyd 1965), so the response appears to be
due to local action of the hypoxia on the artery itself.
It is also known that it is the P02 of the alveolar gas,
not the pulmonary arterial blood, which chiefly
determines the response (Duke 1954, Lloyd 1965).
This can be proved by perfusing a lung with blood of
a high PO2 while keeping the alveolar P0z low. Under
these conditions the response is well seen.
The site of the vasoconstriction is still not certain
but several pieces of evidence suggest that it is
predominantly in the small pulmonary arteries (Kato
and Staub 1966, Glazier and Murray 1971). Some
studies indicate that the alveolar vessels may be
partly responsible for the increased resistance, and
contractile cells have been described in the
interstitium of the alveolar wall, which could
conceivably distort capillaries and increase their
resistance (Kapanci et al. 1974). However, the fact
that the pulmonary arterial pressure can increase to
levels of 50 mmHg or more in subjects at high
altitude without the occurrence of pulmonary edema
suggests that the main site of constriction is
upstream of the pulmonary capillaries from which
the fluid leaks.
Having said this, it is also true that pulmonary
edema does occur at high altitude from time to time
(Chapter 19) and a likely mechanism is that the
hypoxic pulmonary vasoconstriction is uneven
(Hultgren 1978), with the result that those capillaries
which are not protected from the increased
pulmonary arterial pressure develop ultrastructural
damage to their walls. This results in a high
permeability type of edema. This topic is considered
in more detail in section 19.7.5.
As indicated earlier, the mechanism of hypoxic
pulmonary vasoconstriction is still unclear.
Chemical mediators which have been studied in the
past include catecholamines, histamine, angiotensin
and prostaglandins (Fishman 1985). Recently, a great
deal of interest has been generated by the observation
that inhaled nitric oxide reverses hypoxic pulmonary
vasoconstriction.
Nitric oxide has been shown to be an endotheliumderived relaxing factor for blood vessels (Ignarro et
al. 1987). Nitric oxide is formed from L-arginine via
catalysis by endothelial nitric oxide synthase (eNOS)

and is a final common pathway for a variety of biological processes (Moncada et al 1991). Nitric oxide
activates soluble guanylate cyclase, which leads to
smooth muscle relaxation through the synthesis of
cyclic GMP. Several studies suggest that potassium
ion channels in smooth muscle cells may be involved,
leading to increased intracellular concentration of
calcium ions. Nitrovasodilators, such as nitroprusside and glycerol trinitrate, which have been used
clinically for many years, are thought to act by these
same mechanisms.
Inhibitors of nitric oxide synthesis have been
shown to augment hypoxic pulmonary vasoconstriction in isolated pulmonary artery rings (Archer
et al. 1989), and attenuate pulmonary vasodilatation
in intact lambs (Fineman et al. 1991). Inhaled nitric
oxide reduces hypoxic pulmonary vasoconstriction
in humans (Frostell et al. 1993) and sheep (Pison et
al. 1993), and lowers pulmonary vascular resistance
in patients with high altitude pulmonary edema
(HAPE) (Anand et al. 1998). The required inhaled
concentration of nitric oxide is extremely low (about
20 (ig g~!), and the gas is highly toxic at high concentrations. The recognition of the role of nitric oxide
has opened up a new era in our understanding of
hypoxic pulmonary vasoconstriction.
Hypoxic pulmonary vasoconstriction has the
effect of directing blood flow away from hypoxic
regions of lung, caused, for example, by partial
obstruction of an airway. Other things being equal,
this will reduce the amount of ventilation/perfusion
inequality in a lung and limit the depression of the
arterial P02. This is a useful response. However, the
pulmonary hypertension that is seen at high altitude
appears to have no value except to cause a more
uniform topographical distribution of blood flow
(Dawson 1972). In fact, the improvement in ventilation/perfusion relationships resulting from this
more uniform distribution of blood flow is trivial in
terms of overall gas exchange (West 1962b) and we
must conclude that the pulmonary hypertension of
high altitude has no useful function, but in fact is
deleterious because it is responsible for the occurrence of HAPE. As stated earlier, the evolutionary
pressure for the mechanism of hypoxic pulmonary
vasoconstriction presumably comes from its value in
the perinatal period.
The lungs of long-term residents at high altitude
show changes related to pulmonary hypertension
(Heath and Williams 1995). Bands of smooth muscle

Pulmonary circulation 93

Figure 7.12 Histological section of a pulmonary arteriolefrom a

Quechua Indian living at high altitude in the Peruvian Andes.
Muscle tissue is seen between internal and external elastic
laminae. Normally there is a single elastic lamina and no muscle
tissue in a vessel of this size at sea level. (Elastic van Gieson stain x
375J (From Heath and Williams 1977.)

develop in the small pulmonary arteries (arterioles)

of approximately 500 |J,m diameter which normally
have a wall consisting only of a single elastic lamina.
The result is that these small vessels develop a media
of circularly oriented smooth muscle bonded by
internal and external elastic laminae (Figure 7.12).
These changes are associated with narrowing of the
lumen and an increase in pulmonary vascular resistance. Medial hypertrophy of the parent muscular
pulmonary arteries is not a common feature (AriasStella and Saldana 1963), though it occurs in some
individuals (Wagenvoort and Wagenvoort 1973).
Occlusive intimal fibrosis apparently does not occur.
However, longitudinal muscle fibers developing in
the intima of pulmonary arterioles in highlanders
have been described (Wagenvoort and Wagenvoort
1973). Some authors have also described an increase
in mast cell density in experimental animals exposed
to long-term hypoxia (Kay et al. 1974). This is of

interest because at one stage it was thought that

mediators from mast cells, for example histamine,
might be involved in the vasoconstrictor response.
These structural changes are consistent with the
fact that the pulmonary arterial pressure of high
altitude natives falls only slightly (by 15-20 per cent)
when oxygen is breathed (Penaloza et al 1962).
These authors showed that inhabitants of Cerro de
Pasco (4330 m) who moved to sea level had their
mean pulmonary arterial pressure halved from 24 to
12 mm Hg after 2 years of residence at sea level. The
fact that lowlanders who are exposed to high altitude
for 2-3 weeks develop pulmonary hypertension
which is not completely reversed by 100 per cent
oxygen breathing (Groves et al. 1987) suggests that
their pulmonary blood vessels may also have
developed some increased smooth muscle.
The structural changes that occur in pulmonary
arteries when the pulmonary arterial pressure is
raised as a result of exposing an animal to hypoxia
are referred to as vascular remodeling (Riley 1991).
Meyrick and Reid (1978, 1980) exposed rats to half
the normal barometric pressure for 1-52 days. The
result was an increase in pulmonary artery pressure
as a result of hypoxic pulmonary vasoconstriction.
After 2 days they saw the appearance of new smooth
muscle in small pulmonary arteries, and after 10 days
there was doubling of the thickness of the media and
adventitia of the main pulmonary artery due to
increased smooth muscle, collagen and elastin, and
also edema. There was some recovery after 3 days of
normoxia, and after 14-28 days the thickness of the
media was normal. However, some increase in
collagen persisted up to 70 days.
The molecular biology of the responses of the
pulmonary blood vessels has been studied by several
groups. Mecham et al. (1987) looked at the response
of the pulmonary arteries of newborn calves to
alveolar hypoxia. There was a twofold to fourfold
increase in elastin production in pulmonary arterial
wall and medial smooth muscle cells. This was
accompanied by a corresponding increase in elastin
messenger RNA consistent with regulation at the
transcriptional level. Poiani etal. (1990) exposed rats
to 10 per cent oxygen for 1-14 days. Within 3 days of
exposure there was increased synthesis of collagen
and elastin, and an increase in mRNA for 0^(1) procollagen.
Tozzi et al. (1989) placed rat main pulmonary
artery rings in Krebs-Ringer bicarbonate. They

94 Cardiovascular system

applied mechanical tension equivalent to a transmural

pressure of 50 mm Hg for 4 h, and found increases in
collagen synthesis (incorporation of [14C]-proline),
elastin synthesis (incorporation of [14C]-valine),
mRNA for 0^(1) procollagen, and mRNA for protooncogene v-sz's. The last may implicate plateletderived growth factor (PDGF) or transforming
growth factor (TGF)-fS as a mediator. They were able
to show that these changes were endothelium
dependent because they did not occur when the
endothelium was removed from the arterial rings.
It is possible that this vascular remodeling is a
general property of pulmonary vascular endothelium. It has been pointed out that the capillary
wall has a dilemma in that it must be extremely thin
for gas exchange but immensely strong to withstand
the wall stresses when the capillary pressure rises
during heavy exercise (West and Mathieu-Costello
1992b). There is good evidence that the extracellular
matrix of the blood-gas barrier, at least on the thin
side, is responsible for its strength, and it is known
that in mitral stenosis, where the capillary pressure
rises over long periods of time, there is an increase in
thickness of the extracellular matrix (Kay and
Edwards 1973). Thus it may be that the capillary is
continually regulating the structure of the wall in
response to the capillary pressure which is sensed by
the endothelium. The capillaries appear to be the
most vulnerable vessels in the pulmonary circulation
when the pressure rises. Thus vascular remodeling,
which has been largely studied in larger blood vessels,

may be a general property of the pulmonary

vasculature, and its evolutionary advantage may be
primarily to protect the walls of the capillaries.
The mechanism of capillary wall remodeling in
response to increased wall stress has been the subject
of three recent studies. Berg et al. (1997) exposed
rabbit lungs to high levels of lung inflation because
this is known to increase the wall stress of pulmonary
capillaries (Fu et al. 1992). Increased gene expression
for ocelli) and OC2(IV) procollagens, fibronectin,
basic fibroblast growth factor (bFGF), and TGF-pl
was found in peripheral lung parenchyma compared
with control animals in normal states of lung
inflation. However, mRNA levels for a, (I) procollagen and vascular endothelial growth factor
(VEGF) were unchanged. Parker et al. (1997) raised
capillary transmural pressure by increasing the
venous pressure in isolated perfused rat lungs. There
were significant increases in gene expression for oc^I)
and OC,(III) procollagens, fibronectin and laminin
compared with controls in which the venous pressure was normal. Berg et al. (1998) placed rats in
10 per- cent oxygen for periods from 6 h up to
10 days, and the hypothesis was that because the
pulmonary vasoconstriction caused by alveolar
hypoxia may be uneven, some capillaries may be
exposed to a high transmural pressure, and therefore
have increased wall stress. Levels of mRNA for
OC2(IV) procollagen increased sixfold after 6 h of
hypoxia, and sevenfold after 3 days of hypoxia.
However, the levels decreased after 10 days of

Figure 7.13 Twelve-lead

electrocardiogram obtained at Camp 2
(6300 m) and about 3 months after return
of the subject to sea level. Sinus
tachycardia and diffuse T-wave flattening
present at altitude; the T waves in leads V2
and V3 exhibit terminal inversion. (From
Karlinerelsl. 1985.)

Pulmonary circulation 95

exposure. mRNA levels for PDGF-B, oc^I) and

a3(III) procollagens and fibronectin also increased.
All the above results are consistent with capillary wall
remodeling in response to increased wall stress, but
the overall picture is still far from clear.
The environment of the human fetus is similar in
some respects to that of the high altitude dweller in
that the arterial P0 is less than 30 mm Hg, based on
measurements on experimental animals (Itskovitz et
al. 1987). The fetus also has pulmonary hypertension
because the pulmonary artery is connected to the
systemic arterial system through the patent ductus
arteriosus. In keeping with this, the fetal lung shows
a high degree of muscularization, of the pulmonary
arteries. Babies born at a high altitude show persistence of this muscularization, whereas the pulmonary
arteries of those born at sea level assume the adult
appearance after only a few weeks.

7.53

6300 m, and again at sea level. A total of 19 subjects

were studied, though complete data were not
obtained from all. Resting heart rate increased from a
mean of 57 at sea level to 70 at 5400 m and 80 at

Right ventricular hypertrophy

The pulmonary hypertension of high altitude causes

right ventricular hypertrophy both in acclimatized
lowlanders and in high altitude natives. In one study
of children of 2-10 years of age it was shown that at
sea level the ratio of left to right ventricular weights
was about 1.8, whereas at high altitude it was less
than 1.3 (3700-4260 m) (Arias-Stella and Recavarren
1962). Experimental studies on rats exposed to an
altitude of 5500 m showed that they developed right
ventricular hypertrophy within 5 weeks (Heath et al.
1973).
Data on acclimatized lowlanders are not generally
available, though there is abundant indirect evidence
of right ventricular hypertrophy from electrocardiographic changes (section 7.5.4). Occasionally,
climbers returning from high altitude have shown
evidence of right heart enlargement on the chest
radiograph (Pugh 1962a).
Figure 7.14 (a) Ms Phantog, deputy leader of the 1975 Chinese

7.5.4

Electrocardiographic changes

Electrocardiographic changes are considered here

because most of the changes are attributable to
pulmonary hypertension. An extensive study was
carried out during the 1981 American Medical
Research Expedition to Everest (Karliner et al. 1985)
when recordings were made at sea level, 5400 m,

Expedition to Everest, lying under the tripod that was placed on the
summit Lead 1 of her electrocardiogram was telemetered to Base
Camp (from Another Ascent of the World's Highest Peak,
Qomolangma 1975). (b) Standard lead 1 of the ECG of Ms Phantog
from 50 m altitude to 8848 m (Everest summit) and back to 50 m:
a, 50 m; b, 500 m; c, 6500 m; d, 8848 m (summit); e, back at
500 m; f, 1 month after returning to 50 m; g, 2 months after
returning to 50 m; h, 3 months after returning to 50 m. No obvious
changes are seen. (From Zhongyuan et al. 1980.)

96 Cardiovascular system

6300 m (compare section 7.3.2). The amplitude of

the P wave in standard lead 2 of the electrocardiogram increased by over 40 per cent from sea level to
6300 m, consistent with right atrial enlargement.
Right axis deviation of the QRS axis was seen. The
mean frontal plane QRS axis increased from +64 to
+78 at 5400 m and +85 at 6300 m. Three subjects
showed abnormalities of right bundle branch conduction at the highest altitude and three others
showed changes consistent with right ventricular
hypertrophy (posterior displacement of the QRS
vector in the horizontal plane). Seven subjects
developed flattened T waves and four showed
T-wave inversions (Figure 7.13). All the changes
returned to normal in tracings obtained at sea level
after the expedition.
Other investigators have reported similar findings
in acclimatized lowlanders, though generally on
smaller numbers or at lower altitudes. Milledge (1963)
made measurements during the 1960-1 Himalayan
Scientific and Mountaineering Expedition and
reported data on subjects who spent several months
at an altitude of 5800 m. In addition some recordings

were made as high as 7440 m in climbers who never

used supplemental oxygen. He found T-wave inversions on the right pre-cordial leads in six subjects; two
had left pre-cordial T-wave inversion as well. Oxygen
breathing had no effect on these changes. Das et al.
(1983) reported on over 40 subjects who were rapidly
transported to either 3200 or 3771 m. There was a tendency for a rightward axis shift which, interestingly,
tended to resolve in most subjects after 10 days at high
altitude.
A particularly remarkable measurement was made
on Ms Phantog, deputy leader of the successful 1975
Chinese ascent of Mount Everest. She lay down on
the summit under the newly erected tripod while her
standard lead 1 was telemetered down to Base Camp
(Figure 7.14). Note that there were no changes from
sea level to 8848 m and back again (Zhongyuan et al.
1980). Other electrocardiographic studies at high
altitude include those made by Penaloza and
Echevarria (1957), Jackson and Davies (1960),
Aigner et al (1980), Kapoor (1984), Halperin et al.
(1998), Malconian et al. (1990) and Chandrashekhar
etal (1992).

8
Hematology
8.1
8.2
8.3
8.4

Introduction
Regulation of hemoglobin concentration
Effect of altitude on plasma volume
Altitude and erythropoiesis

97
98
101
102

8.5
8.6
8.7

Altitude and hemoglobin concentration

Platelets and clotting at altitude
White blood cells

103
106
106

SUMMARY

8.1

INTRODUCTION

The best known aspects of altitude acclimatization

are the increase in red cell numbers per unit volume
and the increase in hemoglobin concentration. These
are achieved, initially, by a reduction in plasma volume and later by an increase in red cell mass (RCM).
Hypoxia induces the release of erythropoietin (EPO),
which stimulates the bone marrow to increase red
cell output. The EPO gene is induced by hypoxia
through a nuclear factor, the hypoxia-inducible factor-1 (HIF-1). Although EPO levels rise within a few
hours, the increase in RCM takes weeks and only
reaches a steady state after some 6 months. Plasma
volume is restored to near sea level values after a few
weeks. The rise in hemoglobin concentration is
roughly linear with altitude and is similar in acclimatized lowlanders and residents of high altitude,
though with wide individual variation. Evidence is
accumulating that Tibetans have lower hemoglobin
concentration than Andean residents at similar altitudes. Extreme polycythemia among residents or
lowlanders staying at altitude for many years, is considered pathological and termed chronic mountain
sickness (Chapter 21).
The effect of altitude on white cells has been little
studied. Changes are variable, though increase in
CD 16 natural killer cells has been reported.
The effects of altitude on platelets and clotting are
considered in Chapter 22.

Probably the best-known adaptation to high altitude

is the increase in the number of red cells per unit volume of blood. Paul Bert suggested in his book La
Pression Barometrique (1878) that adaptation to high
altitude might include an increase in the number of
red cells and in the quantity of hemoglobin. Thus the
blood would be able to carry more oxygen. A few
years later he was sent samples of blood from a number of domestic animals from La Paz, Bolivia
(3500 m). He showed that these samples combined
with 16.2-21.6 volumes of oxygen per 100 volumes
of blood compared with 10-12 volumes per cent in
the blood of animals in France (West 1981).
Viault, in 1890, made the first blood counts of men
at high altitude. His own blood count at sea level in
Lima was 5 million mL"1 and after 3 weeks at
Morococha, a mining township at 4372 m in the
Andes, the value had increased to 7.1 million mL"1.
We now know that most of this increase, early in altitude exposure, would be due to reduced plasma volume rather than an increase in RCM. Viault found
these elevated counts present in a companion doctor
from Lima and also in a number of the local Indian
residents at altitude. He also noted that in a male
llama the value was 16 million mL~3. He called the
llama, Tanimal par excellence des grandes altitudes',
although, in fact, since the llama has very small red
cells, the hemoglobin concentration of the blood is

98 Hematology

the same as in humans. In 1891 Viault published further observations which confirmed Bert's work on
the oxygen-carry ing capacity of high altitude
animals. He showed in two sheep and one dog that
their oxygen-carrying capacity was increased compared with similar animals in France.
Since then, almost all expeditions with any pretence at carrying out physiological research at high
altitude have observed this increase in red cell count,
packed cell volume, or hemoglobin concentration.
The increase in red cell number and hemoglobin
concentration increases the oxygen-carrying capacity
in such a way that, up to about 5300 m, fully acclimatized humans have the same oxygen content in
their blood as at sea level (Figure 8.1).
The increased carrying capacity compensates for
the reduced oxygen saturation. This affords physiology teachers a classical example of beneficial adaptation. However, it is unlikely that the mechanism of
this adaptation evolved primarily to serve humans at
high altitude (section 8.2.1). The extent to which
benefit can be gained by increasing hemoglobin concentration is fairly limited and indeed has been questioned as beneficial at all (Winslow and Monge 1987,
p. 203; section 8.5.4).

Figure 8.1 The oxygen content of arterial blood in an acclimatized

subject at 5300 m and at sea level.

8.2 REGULATION OF HEMOGLOBIN

CONCENTRATION
The hemoglobin concentration and packed cell volume (PCV) depend upon the ratio of the RCM to
plasma volume (PV). These two variables are regulated by different mechanisms. The rate of formation
of red cells (erythropoiesis) and their rate of loss
determine the RCM.
Red blood cells are lost by death (their natural
length of survival is about 120 days), or by hemorrhage. Their death can be hastened by a variety of
pathological states such as hemolytic anemia.
Erythropoiesis can be impaired by various deficiencies, such as iron or vitamin B12 (needed for hemoglobin synthesis), or by disorders of the bone
marrow. In the absence of these, erythropoiesis is
controlled by the level of the hormone EPO.
8.2.1

EPO and its regulation

EPO is produced mainly in the kidney, though

10-15 per cent of total production is in the liver
(Erslev 1987). The gene coding for the hormone has
been cloned and expressed in cultured cells, allowing
for sufficient material to be produced for clinical
studies. It has been shown to stimulate erythropoiesis
in patients anemic with end-stage renal failure
(Winearls et al. 1986).
The two classical stimuli for EPO secretion are
hypoxia and blood loss, both of which result in tissue hypoxia. Of the two, blood loss is probably
more important in evolutionary terms of survival
of the organism. Blood loss is a far more common
danger than is chronic hypoxia, and of course this
system is no defense against acute hypoxia. The
stimulus to EPO secretion is hypoxia at some tissue
site, probably in the kidney, possibly identical with
the site of production of the hormone. It is
instructive to compare this system with another
hypoxia-sensitive system in the body, the hypoxic
ventilatery response (HVR), mediated mainly via
the carotid body:
The HVR appears in seconds after a step change in
arterial P02 whereas there is no detectable rise in
EPO concentration for over an hour, 114 min
when exposed suddenly to 3000 m or 84 min at
4000 m (Eckardt etal. 1989).

Regulation of hemoglobin concentration 99

The carotid body is sensitive to reduction in P02

rather than oxygen content of the blood.
Therefore it does not respond to anemia, whereas
anemia stimulates EPO secretion.
From these observations it is assumed that,
whereas the carotid body response is to arterial P02>
the sensing of P02 for EPO secretion is at the venous
or tissue level. In patients with a reversed flow
through a patent ductus arteriosus, there is cyanosis
(hypoxia) in the lower half of the body only. These
patients have high hemoglobin concentration, indicating that the P02 sensor is in the lower half of the
body, presumably in the kidney. Fisher and
Langston (1967) showed that EPO was produced in
the juxtaglomerular apparatus in the kidney and
that hypoxia was sensed there, since the isolated
dog kidney increased its output of EPO when perfused with hypoxic blood.

8.2*2

Regulation of plasma volume

The central control of PV is probably by a feedback

loop involving atrial natriuretic peptide (ANP) and
the right atrium (Laragh 1985). ANP is released in
response to stretching of the right atrium.
Physiologically, this is produced by increased right
atrial pressure. This in turn may be due to shifts of
blood volume from the periphery, mainly the lower
body, or by increase in the total blood volume (i.e.
PV). ANP causes the kidney to excrete sodium and
with it water, thus reducing the PV. This simple feedback loop is shown in Figure 8.2.

Figure 8.2 The regulation of plasma volume (PV) by atrial

natriuretic peptide (ANP).

We can add on to this simple system a host of

other factors which affect PV (Figure 8.3):
Hydration and dehydration will obviously affect
PV, along with all other body fluid compartments.
The vascular capacity is determined by the tone of
the vessels, especially the venous capacitance
vessels and vessels in the skin. Vessel tone, in
turn, depends on a number of factors, such as
temperature and catecholamine levels. Peripheral
vasoconstriction shifts blood from the periphery
to the center, raising right atrial pressure and
stimulating ANP release. Vasodilatation has the
opposite effect. A change in vascular capacity
also has a more direct effect on PV by shifting
the balance of forces in the Starling equation.
Vasodilatation will tend to reduce the intravascular pressure, favoring inward movement of
fluid at the tissue level; vasoconstriction has the
opposite effect. It is this direct effect that is
depicted in Figure 8.3.
Other factors that cause a shift of blood volume
to the center include lying down, lower body
immersion and G-suits. Zero gravity experienced by astronauts has a similar effect. Right
atrial pressure is raised and ANP excretion is
increased. Conversely, the upright position
tends to shift volume away from the center to
the lower body, reducing right atrial pressure
and inhibiting ANP release.
Antidiuretic hormone (ADH) secretion will
result in increased PV by retaining water, but
there is another feedback loop involving plasma
osmolality and ADH. If plasma volume increase
is caused by hydration, osmolality falls and
secretion of ADH is inhibited. A water diuresis
then follows which restores the osmolality and
ADH levels rise again. This loop is not shown in
Figure 8.3, to avoid overloading the diagram.
The sodium status is important in determining
the PV. A high sodium intake will tend to cause
water retention and increase PV. Increase in
ANP will then compensate for this. Stimulation
of the renin-angiotensin-aldosterone system
causes sodium retention with the same result.
Renin is stimulated by posture (the upright
position) and by exercise, though posture and
exercise have effects on PV via other mechanisms (section 8.2.3).

100 Hematology

Figure 8.3 Some of the factors affecting

plasma volume (PV) and its regulation by
atrial natriuretic peptide (ANP),
antidiuretic hormone (ADH), aldosterone
(Aldo) and vascular capacity.

8,23

Posture and plasma volume

Seventy per cent of the blood volume is below the

heart in the upright position and, of this, 75 per cent
is in the distensible veins. On standing up, 500 ml of
additional blood enters the legs, so that reflex tachycardia and vasoconstriction are essential to prevent
fainting. Vasoconstriction maintains the blood pressure and reduces flow, especially to the skin, muscles,
kidneys and viscera. The capillaries are exposed to
the hydrostatic pressure of the column of venous
blood. This will tend to increase filtration of fluid out
of the vascular compartment, and hemoconcentration would be expected. Numerous investigators
from Thompson et al. (1928) onwards have confirmed these theoretical expectations. Thompson et
al. found a reduction of plasma volume of 15 per cent
on assuming the upright position, but the magnitude
of this effect is variable and is influenced by many
factors, including environmental and subject temperature, state of hydration, etc.
The effect of posture is therefore significant and

needs to be taken into account when considering the

effect of other variables such as hypoxia or exercise
on plasma volume.

8.2.4

Exercise and plasma volume

Exercise can have an important effect on plasma volume and hence on hemoglobin concentration and
PCV, but the effect varies according to the intensity,
duration and type of exercise. The temperatures of
the environment and the subject modify the effect. It
is also modified by posture (section 8.2.3). This is
because temperature and posture affect the skin
blood flow and hence the distribution of cardiac output to skin, working muscles, kidneys, splanchnic
area, etc. This, in turn, affects the capillary and
venous pressures in these areas and hence the balance of forces in the Starling equation. Many studies
on the effect of exercise have ignored the effect of
posture and have taken control samples in a different
posture from exercise samples.

Effect of altitude on plasma volume 101

Harrison (1985) has reviewed the literature and,

with a number of reservations, comes to the conclusion that, for bicycle ergometer exercise, there is a
reduction in the PV soon after starting exercise.
This reduction is proportional to the intensity of
exercise or, more precisely, to the rise in atrial pressure. Thereafter there is little change with continued exercise at normal room temperature but in
high temperatures there is a further reduction in PV
with time. However, these laboratory studies tend
to look at fairly high intensity exercise (greater than
50 per cent Vo2max) fr periods of up to an hour or
two.
Exercise on mountains is taken over periods of
many hours and may go on day after day. The availability of fluid for drinking will obviously make a difference. If this is not available, dehydration will
certainly reduce PV, but usually fluid is available to
climbers and exercise heat stress can usually be
avoided. Under these circumstances of exercise of 8 h
or more at normal climbing rates (i.e. up to about
50 per cent V02max but averaging much less) an
increase in PV is found. Pugh (1969) found an
increase in blood volume of 7 per cent after a 28 mile
hill walk. Williams et al. (1979) found PV increased
progressively for 5 days of strenuous daily hill walking to reach a 22 per cent expansion. Both these studies were carried out under cold conditions and
subjects avoided both overheating and cold stress.
The changes in PV, interstitial and intracellular volumes are shown in Figure 8.4.
The mechanism is probably via activation of the
renin-angiotensin-aldosterone system, which results
in sodium retention and thus a general expansion of
the extracellular fluid (ECF) volume including the
PV (Milledge etal. 1982). Under these circumstances
the PCV decreased from a mean of 43.5 per cent to
37.9 per cent after 5 days of exercise.

83
EFFECT OF ALTITUDE ON PLASMA
VOLUME
During the first few hours of altitude exposure the
effect on PV is variable and data are scanty. In the
field, the effect of hypoxia may be overshadowed by
that of cold, dehydration and exercise but it seems
that those subjects free from acute mountain sickness
(AMS) have a diuresis and contract their PV. Singh et

Image Not Available

Figure 8.4 The effect of five consecutive days' strenuous hill

walking on body fluid compartments. The changes are calculated
from changes in packed cell volume, and sodium and water
balances. (Reproduced with permission from Williams et al. 1979.)

al. (1990) found a reduction in PV from 40.4 mL kg"1

at sea level to 37.7 mL kg"1 on day 2 at 3500 m, and
37.0 mL kg-1 on day 12. Wolfel etal (1991) reported
similar changes in PV on ascent to 4300 m; PV fell
from 48.8 mL kg"1 to 42.5 mL kg-1 on arrival at altitude and to 40.2 mL kg-1 by day 21. Some caution
must be exercised in the interpretation of these studies in the light of a recent study by Poulson et al.
(1998). They measured the change in PV of 10 subjects on being airlifted to the Vallot observatory
(4350 m) using both the Evans' blue and the carbon
monoxide methods. Twenty-four hours after arrival
at altitude they found the expected reduction in PV
with the carbon monoxide method (350 mL reduction) but not with the Evans' blue method (30 mL
reduction). A possible explanation is that hypoxia
induced an increase in capillary permeability to albumin so that the Evans' blue method, which would
have included this extravascular pool of albumin,
gave a falsely high result.
Subjects with AMS have an antidiuresis and probably expand their PV. Vigorous exercise taken on
getting up to altitude or on arrival will also result in
expansion of the PV, via the renin-aldosterone
system (Milledge etal. 1983d).
Honig (1983) has reviewed the effect of acute
hypoxia on body fluid volumes, especially in animal

102

Hematology

experiments. With exposure to moderate hypoxia

equivalent to altitudes of 3000-6000 m there is a
diuresis and natriuresis. After reviewing possible
mechanisms via effects on the cardiovascular system,
Honig presents evidence, from his own work, that
the carotid body, stimulated by hypoxia, reduces the
reabsorption of sodium by the kidney via neural
pathways. This mechanism has not been demonstrated in humans. (This comprehensive review antedates the recognition of the importance of atrial
natriuretic peptide.)
After this early phase of altitude exposure, there is
a definite reduction in PV over the next few weeks.
Pugh (1964b) found a 21 per cent reduction in PV
after 18 weeks at altitudes above 4000 m in four
members of the 1960-1 Silver Hut Expedition
(Figure 8.5). During the following 7-14 weeks the PV
returned towards control levels, values being on
average 10 per cent less than control when corrected
for changes in body weight.
Sanchez et al. (1970) found altitude residents at
Cerro de Pasco (4370 m) in Peru to have a mean
PV two-thirds that of a group of students at Lima
(sea level). When allowance was made for the
weight difference of the groups they still had a PV
27 per cent less in a blood volume that was
14 per cent greater.

Figure 8.5 Changes in hemoglobin concentration (Hb%), red cell

volume, blood volume and plasma volume in four subjects during
the Silver Hut Expedition: (a) after 18 weeks at between 4000 and
5800 m; (b) after a further 3-6 weeks at 5800 m; (c) after a further
9-14 weeks at or above 5800 m. (After Pugh 1964b.)

8.4

8.4.1

ALTITUDE AND ERYTHROPOIESIS

EPO, HIF-1 and hypoxia

EPO is a hormone secreted by peritubular cells in the

kidney. It is one of a number of gene products whose
transcription is stimulated by hypoxia. These include
aldolase A, enolase-1 glucose transporter-1, lactate
dehydrogenase and phosphofructokinase, all involved
with glycolysis; inducible nitric oxide synthase and
heme oxygenase, involved with vasodilatation; and
vascular endothelial growth factor which promotes
angiogenesis. The link between hypoxia and the
induction of the genes for all these proteins involves
the recently discovered HIF-1. HIF-1 is a nuclear factor induced by hypoxia which binds to the promoter
part of these genes. It was first identified as a nuclear
factor that bound to the hypoxia response element of
the EPO gene (Semenza et al 1998). The other
hypoxia-induced genes all have similar core binding
sites for HIF-1.

8.4.2 Altitude and serum EPO

concentration
Until about 1980, measurements of EPO in blood
were by bioassays which could not detect the hormone until its concentration was above normal sea
level values. Therefore, earlier work often relied on
more indirect indices of erythropoietic activity such
as intestinal iron absorption or reticulocyte counts.
The latter is a rather late effect. Intestinal iron
absorption has been shown to be independent of
EPO and to be promoted as a direct effect of hypoxia
rather than secondary to plasma iron turnover or
erythropoietic activity (Raja etal. 1986). On going to
altitude there is an elevation of EPO concentration in
the first 24-48 h (Siri et al. 1966, Albrecht and Little
1972). Newer methods of EPO estimation using
radioimmunoassays are sensitive to levels of EPO
well below the normal range (13-37 mlU mL"1).
Using this type of assay it has been found that serum
immunoreactive EPO concentration (SiEp) begins to
rise within 2 h of hypoxic exposure, depending on
the altitude (Eckardt etal. 1989), and reaches a maximum at about 24-48 h. Thereafter, it declines to
reach values not measurably different from controls
after about 3 weeks (Milledge and Cotes 1985). This
is shown in Figure 8.6, which also shows the rise in

Altitude and hemoglobin concentration 103

normoxia is restored. For instance, 120 min breathing 10 per cent oxygen caused SiEp to rise just after
normoxia was restored and the rise continued for a
further 120 min (Knaupp etal 1992).
It will be seen from Figure 8.6 that PCV continues
to rise after SiEp falls to near control values. The rise
in RCM continues even longer (section 8.4.3). In
patients with polycythemia secondary to hypoxic
lung disease the SiEp was found to be within the normal range in over 50 per cent of patients (Wedzicha
et al. 1985). A continued erythropoiesis when levels
of SiEp have fallen to near control values is unexplained.

Image Not Available

8.43

Figure 8.6 The effect of going to altitude on the serum

erythropoietin concentration. The top panel shows the
altitude/time profile for the eight subjects. The dotted line

Altitude and red cell mass

The result of increased erythropoiesis at altitude is an

increase in RCM since the life span of the red cell is
unchanged (Berlin et al. 1954). Figure 8.5 shows the
rise in RCM, which is quite slow at first but continues
for a long time. After about 6 months at altitudes
above 4000 m it had increased by a mean of
50 per cent in absolute terms or 67.5 per cent when
corrected for loss of body weight. By this time the
blood volume had increased over control by
7.3 per cent or 22.8 per cent corrected for body
weight (Pugh 1964a) (Figure 8.5). Sanchez et al.
(1970) found altitude residents in the Andes to have
a RCM 83 per cent greater than sea level residents
when corrected for weight difference.

indicates ascent above base camp between blood samples. Note,

the samples at 30 days were taken at 5500 m after four sample
times at base camp (4500 m). Mean packed cell volume (PCV) is
shown in the center panel and mean erythropoietin concentration

8.5 ALTITUDE AND HEMOGLOBIN

CONCENTRATION

in the lower panel. C, control, sea level; K, Kashgar (1200 m); L,

Karakol lakes (3500 m). (Reproduced with permission from
Milledge and Cotes 1985.)

PCV on going to altitude. A similar rapid rise and

decline was found by Gunga et al (1994) at the modest altitude of 2315 m.
The rise in SiEp with altitude shows great individual variability. In a study in the Andes, Richalet et al.
(1994) found the increase to range from threefold to
134-fold in their group of subjects 1 week after
arrival at 6540 m.
Figure 8.6 also shows that, even after 3 weeks
above 4500 m, a rise in altitude to 5500 m caused
another rise in SiEp. Quite a short pulse of hypoxia
initiates a rise in SiEp, which continues after

8.5.1
Lowlanders going from sea level
to altitude
The combined effect of changes in PV and RCM
results in an increase in hemoglobin concentration.
This increase allows more oxygen to be carried per
liter of blood at any given oxygen saturation. The
price paid for this gain in oxygen capacity, however,
is an increase in viscosity of the blood with the attendant increased risk of thrombosis (Chapter 22).
As discussed in section 8.3, the initial rise in hemoglobin concentration during the first few days and
weeks at altitude is largely a result of reduction in
PV. The hemoglobin concentration rise is roughly

104 Hematology

exponential, leveling out at about 6 weeks at a given

altitude. However, after that, the RCM continues to
rise but so does the PV so that hemoglobin concentration remains approximately constant (Figure 8.5).
Pugh (1964c) reviewed results from five expeditions
(51 observations in 40 subjects) and concluded that
the hemoglobin concentration after about 6 weeks at
altitude averaged 20.5 g dL"1. It was independent of
altitude above 5500 m. Winslow et al. (1984), reviewing hemoglobin concentration values from the 1981
American Everest expeditions and two previous
Everest expeditions, found the range of mean values
was 17.8-20.6 g dL-1 at altitudes of 5350-6300 m, with
no correlation between altitude and hemoglobin concentration within this altitude range.

8.5.2

Residents at altitude

Figure 8.7 shows the rise in hemoglobin concentration with altitude in residents of high altitude from
North and South America and Asia. Andean subjects
have been reported to have values in the region of
22 g dL-1 at altitudes of 4300-4500 m (Talbott and
Dill 1936, Dill et al. 1937, Merino 1950). However,

Figure 8.7 The effect of altitude on hemoglobin concentration in

male residents at altitude: , from the Tien Shan; D, from
Colorado mining camps; O, from south Indian hill towns; , from
the Andes; A from Nepal (Sherpas); A, climbers after 3 months or
more at altitude.

these studies may include subjects who would now

be considered to have chronic mountain sickness.
More recent publications from South America give
mean values nearer 20 g dL-1 (Penaloza et al. 1971).
In Sherpa subjects hemoglobin concentration is
lower, a mean of 17 g dL"1 at 4000 m is given by
Adams and Strang (1975) and of 16.2 g dL-1 by
Morpurgo et al. (1976). In this case the possibility
that some subjects may be iron deficient cannot be
ruled out. Morpurgo et al. argue that it represents
greater adaptation. It is estimated that Tibetans have
been resident at high altitude for perhaps
100 000 years, compared with about 20 000 years for
Andean highlanders. However, results in residents of
the Tien Shan and Pamirs by Son (1979) give values
closer to those from South America (Figure 8.7) and
would seem not to support this hypothesis. A possible explanation for the difference between Andean
residents on the one hand and Sherpas and Tien
Shan/Pamir residents on the other is that the latter
move up and down in altitude more frequently than
do Andean altitude dwellers on the altiplano.
However, recent studies showing Tibetan populations to have lower hemoglobin concentration than
Andean populations suggest there may be a genetic
explanation.
A study from Tibet (Beall et al 1987) demonstrated a hemoglobin concentration of 18.2 g dL"1 in
male and 16.7 g dL"1 in female subjects resident at an
altitude of 4850-5450 m, a value substantially lower
than most results from the Andes at comparable altitude. More recent work by the same group (Beall et
al. 1998) confirms this impression. In this study the
same investigators using the same methods studied
highland populations at altitude in Tibet and Bolivia.
They found Tibetans had significantly lower hemoglobin concentration than the Bolivian highlanders
(15.6 compared to 19.2 g dL-1). They found that
genetic factors accounted for a very high proportion
of the phenotypic variance in hemoglobin concentration in both samples. This recent study is in line
with that of Winslow et al. (1989) who compared
Himalayan natives (Sherpas) to high altitude Andean
natives at similar altitudes in Khundi, Nepal and
Ollague (Chile) at 3700 m. Mean hematocrit values
in Nepal were significantly lower than in Chile (48.4
compared with 52.2 g dL"1). They also found SiEp
concentrations to be higher in the Andean population, indicating that they were functionally anemic
even with the higher hematocrit!

Altitude and hemoglobin concentration 105

White people resident in high altitude towns in

Colorado and acclimatized climbers tend to have
lower hemoglobin concentration than Andeans but
higher than Central Asian residents (Figure 8.7).

8.53

Polycythemia of high altitude

Excessive rise of hemoglobin concentration (i.e.

above 22 g dlr1) is generally considered to be pathological and diagnostic of chronic mountain sickness
(Chapter 21). Both people native to high altitude and
lowlanders resident at high altitude for some years
are at risk of developing this condition. Huang et al.
(1984) report that Han Chinese lowlanders resident
on the Tibetan plateau have a higher incidence of this
polycythemia than Tibetans.

8.5*4 Optimum hemoglobin

concentration
An increase in hemoglobin concentration increases
the oxygen-carrying capacity of blood since each
gram of hemoglobin can carry 1.31 mL of oxygen
(Gregory 1974). The oxygen content of the blood is
the product of capacity and saturation (Sa02) plus the
dissolved oxygen. Thus the increase in hemoglobin
concentration with altitude compensates for a reduction in arterial 5a02. At altitudes up to about 5300 m
this compensation results in an arterial oxygen content approximately equal to that at sea level in those
who are acclimatized (Figure 8.1). However, increasing hemoglobin concentration results in increasing
viscosity (Guyton etal. 1973). This increase in viscosity is curvilinear so that, with hemoglobin concentration above about 18 g dL-1, viscosity increases
rapidly. Eventually, this increased viscosity increases
resistance in both systemic and pulmonary circulation, so impeding blood flow, and cardiac output
falls. Oxygen supply to the tissues depends upon oxygen delivery, which is the product of arterial oxygen
content and cardiac output.
These considerations result in the concept of an
optimum hemoglobin concentration below which
oxygen delivery is reduced because of reduction in
oxygen content, and above which it is reduced
because the great increase in viscosity causes a reduction in cardiac output which more than offsets the
increase in content. The major problem in calculating what should be the value of this optimum hemo-

globin concentration is the viscosity of blood and its

effect on cardiac output. Since blood is a nonNewtonian fluid, a single value for viscosity cannot
be assigned to it at any given hemoglobin concentration. The value will vary according to the way it is
measured in vitro. In vivo the effect on resistance will
vary according to the diameter of the vessel under
consideration as well as to whether flow is streamlined or turbulent. Apparent resistance will also vary
with flow. If we ignore the physics and just look at
the effect of changing hemoglobin concentration on
cardiac output in acute animal experiments, these
may not reflect the human situation at altitude where
the vascular system has time to adapt to the polycythemia. The situation is so complex that it is clearly
impossible, on theoretical grounds, to predict an
optimum hemoglobin concentration. Another factor
affecting the apparent viscosity is the deformability,
or filterability, of the red cells. A study by SimonSchnass and Korniszewski (1990) addressed this and
concluded that altitude exposure resulted in an
impaired filterability of red cells which was prevented by the administration of vitamin E.
From clinical experience, it seems that the
extremely high hemoglobin concentration concentration found in chronic mountain sickness
(Chapter 21) and in some patients with chronic
hypoxic lung disease is deleterious. Hemodilution
by venesection alone or with intravenous fluid
replacement results in clinical improvement. In
such patients reduction of PCV from 61 per cent to
50 per cent resulted in a decrease in pulmonary
artery pressure and resistance (Weisse et al. 1975).
Similarly, Winslow et al. (1985) found in Andean
high altitude residents that reduction of PCV from
62 per cent to 42 per cent resulted in increased cardiac output and mixed venous P0r Willison et al.
(1980) found that reducing the PCV from
54 per cent to 48 per cent in patients resulted in an
increase of cerebral blood flow from 44 to
57 mL min"1 per 100 g brain tissue. This would
increase oxygen delivery to the brain by 15 per cent
and was accompanied by an increase in alertness.
In a study of climbers at altitude by Sarnquist et al.
(1986) it was found that hemodilution produced no
improvement or deterioration in measured physical
performance, though there was a small, significant
improvement in psychomotor tests. However, the
subjects studied, though having the highest PCV in
the expedition, were not very polycythemic. Their

106 Hematology

PCV ranged from 57 per cent to 60 per cent before

hemodilution.
There is no obvious correlation between climbing
performance and hemoglobin concentration within
the range of values common on an expedition, at
about 17-22 g dlr1 (Pugh 1964c). Indeed it is usual
to find that climbers who perform best are at the
lower end of this range, suggesting that the optimum
hemoglobin concentration at altitudes above about
5000 m is in the region of 18 g dlr1. Winslow and
Monge (1987, p. 203) conclude that
Excessive polycythemia serves no useful purpose.
Indeed, it is doubtful whether there is any physiologic value in 'normal' polycythemia.

8*5.5 Effect of blood reinfusion on

performance at altitude
At sea level there is no doubt that blood reinfusion
(doping) has a significant effect in improving performance, as measured by V02max, and endurance (Buick
et al. 1980). However, at altitude the situation is less
clear. Young et al. (1996) found no significant benefit from reinfusion of 700 ml of autologous blood in
subjects at 4300 m, though mean values for V02max
were slightly higher on day 1 at altitude in the test
subjects. In a further study by Pandolf et al. (1998)
they found no significant improvement in time for a
3.2 km run in subjects infused with 700 mL of autologous blood. They suggest that the effect diminishes
with increasing altitude and quote earlier work supporting that concept.

8.5.6 Hemoglobin concentration on

descent from altitude
On descent from altitude arterial oxygen saturation
will return to the normal 96-98 per cent and this,

together with the now raised hemoglobin concentration, might be expected to inhibit EPO secretion.
However, Milledge and Cotes (1985) reported that
levels were 66 per cent of control values 8 h and 20 h
after descent following 2 months at or above 4500 m.
This reduced EPO level presumably is sufficient to
reduce erythropoiesis since hemoglobin concentration declines after descent and reaches normal sea
level values after about 6 weeks (Heath and Williams
1995, pp. 61-3).

8.6
PLATELETS AND CLOTTING AT
ALTITUDE
These topics are discussed more fully in Chapter 22.
In summary, it seems that the physiological
response to hypoxia does not involve any important
changes in platelet count or adhesiveness, or in clotting factors. However, there may be changes associated with AMS. If there are changes in clotting
factors, they may represent an effect or a complication of AMS rather than being essential in its genesis.

8.7

WHITE BLOOD CELLS

There seem to be variable changes in total white cell

and differential count on going to altitude. One
study reported a rise in granulocyte count on ascent
to 4300 m (Simon-Schnass and Korniszewski 1990)
and another an increase in certain lymphocyte subsets. CD 16+ or natural killer cells were particularly
increased in seven subjects in a decompression
chamber at 380 mm Hg (Klokker et al. 1993). There
is anecdotal evidence that infections in the skin and
subcutaneous tissues are slow to clear at altitude.
One could speculate that the above finding might
have a bearing on this.

9
Blood gas transport and acid-base balance
9.1
9.2

Introduction
Historical

107
107

9.3
9.4

Oxygen affinity of hemoglobin

Acid-base balance

109
116

SUMMARY

9.1

Alterations of the oxygen affinity of hemoglobin can

alter the oxygen dissociation curve at high altitude
and therefore affect oxygen transport by the blood.
Many animals that live in oxygen deprived environments have high oxygen affinities of their hemoglobin. This is the case in the human fetus. It is
interesting that climbers at extreme altitude increase
their oxygen affinity by extreme hyperventilation
which causes a marked respiratory alkalosis. The
effect of the alkalosis overwhelms the small decrease
in oxygen affinity caused by the increased concentration of 2,3-diphosphoglycerate in the red blood
cells. The P50 of high altitude natives is essentially the
same as the sea level value according to most studies.
However, lowlanders living at high altitude for weeks
tend to have a reduced P50, indicating an increased
oxygen affinity of hemoglobin. An increased oxygen
affinity is advantageous at high altitude because it
assists in the loading of oxygen by the pulmonary
capillaries. The acid-base status of high altitude
natives is a little controversial but many studies have
found a normal arterial pH, indicating a fully
compensated respiratory alkalosis. However,
acclimatized lowlanders usually have an alkaline pH,
indicating that metabolic compensation is not
complete. There is evidence that at extreme altitude,
metabolic compensation for the respiratory alkalosis
is slow, possibly because of chronic volume depletion
caused by dehydration.

Physiological changes in the blood play an important

role in acclimatization and adaptation to high altitude.
In this chapter, the main topics considered are the
changes in oxygen affinity of hemoglobin, and the
alterations of the acid-base status of the blood. The
increase in red cell concentration of the blood was
discussed in Chapter 8, where the regulation of
erythropoiesis was described. Some of the consequences of an altered oxygen affinity of hemoglobin
are alluded to in other chapters, especially Chapter 6
on diffusion of oxygen across the blood-gas barrier,
and Chapter 12 on limiting factors at extreme altitude.

9.2

INTRODUCTION

HISTORICAL

The honor of first plotting the oxygen and carbon

dioxide dissociation curves apparently belongs to
Paul Bert. In his monumental book La Pression
Barometrique he showed the relationships between
partial pressure and blood gas concentration for both
oxygen and carbon dioxide as experimental animals
were exposed to lower and lower barometric
pressures, or as they were gradually asphyxiated by
rebreathing in a closed space (Bert 1878, pp. 135-8 in
the 1943 translation). However, he did not discover
the S-shaped curve for oxygen because he did not
reduce the P0l far enough.

108 Blood gas transport and acid-base balance

The first oxygen dissociation curve over its whole

range was published by Christian Bohr in 1885. The
measurements were made on dilute solutions of
hemoglobin and showed precise hyperbolas (Bohr
1885). They were obviously not compatible with the
data obtained by Bert in experimental animals,
although Bohr did not comment on this. Hufner
(1890) published similar curves for hemoglobin
solutions and argued that a hyperbolic shape would
be expected from the simple equation

An important advance was made by Bohr when

he used whole blood rather than hemoglobin
solutions and this led him to the discovery of the
now familiar S-shaped curve. In the following year
he showed, in collaboration with Hasselbalch and
Krogh, that the dissociation curve was shifted to
the right when the PC02 of the blood was increased,
a phenomenon which came to be known as the
Bohr effect (Bohr et al. 1904). A few years later,
Barcroft found that the addition of acid displaced
the dissociation curve to the right (Barcroft and
Orbeli 1910), and also that an increase in temperature had the same effect (Barcroft and King 1909).
Astrup and Severinghaus (1986) wrote a valuable
historical review of blood gases and acid-base
balance.
It was not long after these important modulators of
the oxygen affinity of hemoglobin were discovered
that physiologists wondered about their importance
at high altitude. For example, when Barcroft
accompanied the first international high altitude
expedition to Tenerife in 1910 he made a special
study of the position of the oxygen dissociation curve,
expecting it to be displaced to the left by the low
arterial PCO2 In the event, he found that the oxygen
dissociation curves of some members of the
expedition at 2130 and 3000 m were shifted to the
right when measured at the normal sea level PC02 of
40 mmHg. However, when he repeated the
equilibrations at the subjects' actual Pco2 at altitude,
the positions of the curves were essentially the same as
at sea level (Barcroft 1911). He concluded that the
decrease in carbonic acid in the blood was
compensated for by an increase in some other acid,
possibly lactic acid. One year later Barcroft went to
Mosso's laboratory, the Capanna Regina Margherita
on Monte Rosa (4559 m), and reported a slight excess
acidity at that altitude (Barcroft et al. 1914).

Some 10 years later, during the 1921-2 AngloAmerican Expedition to Cerro de Pasco in Peru,
Barcroft and his colleagues found an increased
oxygen affinity in acclimatized lowlanders as a result
of the increased alkalinity of the blood. It also
appeared that the increase in affinity was greater than
could be explained by the change in acid-base status
(Barcroft etal 1923).
The question of hemoglobin-oxygen affinity was
examined again on the International High Altitude
Expedition to Chile in 1935. It was found that the
'physiological' dissociation curves (that is, measured
at a subject's own PCo2) were displaced slightly to the
left of the sea level values up to about 4270 m, but
that above that altitude, the curves were displaced
increasingly to the right of the sea level positions
(Keys et al. 1936). Measurements of oxygen affinity
of the hemoglobin were also made at constant pH
and these showed a uniform tendency to a decreased
affinity. The investigators argued that this rightward
shift of the curve might be advantageous at high
altitude because it would facilitate oxygen unloading
to the tissues.
An important discovery was made in 1967 by two
groups working independently (Benesch and
Benesch 1967, Chanutin and Curnish 1967) that a
fourth factor (in addition to -PCo2> pH and temperature) had an important effect on the oxygen affinity
of hemoglobin. This was the concentration of 2,3diphosphoglycerate (2,3-DPG) within the red cells.
This unexpected development raised doubts about
much of the earlier work in which this important
factor had not been controlled. It was subsequently
shown that 2,3-DPG increased at high altitude
(Lenfant et al. 1968) and it was argued that the
resulting decrease in oxygen affinity, which
facilitated unloading of oxygen in the tissues, was an
important part of the adaptation process (Lenfant
and Sullivan 1971).
Until recently relatively little information was available on the oxygen affinity of hemoglobin at extreme
altitude. A few measurements from the Himalayan
Scientific and Mountaineering Expedition for 1960-1
showed that lowlanders who were well acclimatized
to 5800 m had an almost fully compensated respiratory alkalosis (West et al. 1962). Data above this
altitude did not exist.
It was therefore astonishing to find on the 1981
American Medical Research Expedition to Everest
that climbers near the summit apparently had an

Oxygen affinity of hemoglobin 109

extreme degree of respiratory alkalosis which greatly

increased the oxygen affinity of their hemoglobin.
The arterial pH of Pizzo on the Everest summit
exceeded 7.7 as determined from the alveolar PC02
and base excess, both of which were measured
(section 9.4.4).
Turning now to the early history of acid-base
balance at high altitude, it is clear from the above that
it overlaps considerably with a discussion of oxygen
affinity of hemoglobin. However, the reaction of the
blood (as it was called) at high altitude created a great
deal of interest in its own right. Indeed, the acid-base
status of the blood played an important role in early
theories of the control of breathing at high altitude
(Kellogg 1980). As long ago as 1903, Galeotti found
that, in various experimental animals taken to
Mosso's Capanna Regina Margherita laboratory on
Monte Rosa, the amount of acid needed to bring
their hemolyzed blood to a standard pH (determined
from litmus paper) was decreased compared with sea
level (Galeotti 1904). He interpreted this decrease in
titratable alkalinity to mean that there was an
increase in some acid substance in the blood. It was
known that hypoxia caused lactic acid production
(Araki, 1891) and that acid blood stimulated breathing (Zuntz et al. 1906). It was therefore natural to
conclude that this explained the hyperventilation of
high altitude, and that the Pcc,2 fell as a consequence
(Boycott and Haldane 1908). Winterstein (1911)
formulated what became known as the 'reaction
theory' of breathing, which stated that the effects of
both hypoxia and carbon dioxide as stimulants of
ventilation could be explained by the fact that they
both acidified the blood.
The correct explanation of how hypoxia stimulates
ventilation at high altitude had to wait for discovery
of the peripheral chemoreceptors by Heymans and
Heymans (1925). Meanwhile Winterstein (1915)
provided evidence against his own theory when he
showed that, in acute hypoxia, the blood becomes
alkaline rather than acid. A few years later,
Henderson (1919) and Haldane et al. (1919)
correctly explained the alkalinity as being secondary
to the lowered Pcc,2 caused by hyperventilation.
Nevertheless, it is true that even today the control of
ventilation during chronic hypoxia is a subject of
intense research (Chapter 5) and interest still
remains in the acid-base status of the extracellular
fluid (ECF) which forms the environment of the
central chemoreceptors.

93
OXYGEN AFFINITY OF
HEMOGLOBIN
93.1

Basic physiology

Figure 9.1 shows the oxygen dissociation curve of

human whole blood and the four factors that shift
the curve to the right, that is decrease the affinity of
hemoglobin for oxygen. These four factors are
increases in: -PCo2> hydrogen ion concentration,
temperature, and the concentration of 2,3-DPG in
the red cells. Increasing the ionic concentration of
the plasma also reduces oxygen affinity.
Almost all of the change in oxygen affinity caused
by PCQ2 can be ascribed to its effect on hydrogen ion
concentration, although a change in Pcc>2 has a small
effect in its own right (Margaria 1957). The mechanism of the alteration of oxygen affinity through
hydrogen ion concentration (Bohr effect) is through
a change in configuration of the hemoglobin
molecule which makes the binding site less accessible
to molecular oxygen as the hydrogen ion concentration is raised. The molecule exists in two forms:

Figure 9.1 Normal oxygen dissociation curve and its

displacement by increases in H+, PC02, temperature and 2,3diphosphoglycerate (DPG). (From West 1994.)

110 Blood gas transport and acid-base balance

one in which the chemical subunits are maximally

chemically bonded (T form), and another in which
some bonds are ruptured and the structure is relaxed
(R form). The R form has a higher affinity for oxygen
because the molecule can more easily enter the
region of the heme. The approximate magnitudes of
the effects of change in Pcc,2 and pH on the oxygen
dissociation curve are shown in the right insets of
Figure 9.1.
Increase in temperature has a large effect on the
oxygen affinity of hemoglobin, as shown in the top
inset of Figure 9.1. The temperature effect follows
from thermodynamic considerations: the combination of oxygen with hemoglobin is exothermic so
that an increase in temperature favors the reverse
reaction, that is dissociation of the oxyhemoglobin.
The compound 2,3-DPG is a product of red cell
metabolism, as shown in Figure 9.2. An increased
concentration of this material within the red cell
reduces the oxygen affinity of the hemoglobin by
increasing the chemical binding of the subunits and
converting more hemoglobin to the low affinity T
form.
A useful number to describe the oxygen affinity of
hemoglobin is the P50, that is the P02 for 50 per cent
saturation of the hemoglobin with oxygen. The
normal value for adult whole blood at a Pcc,2 of
40 mm Hg, pH 7.4, temperature 37 C, and normal
2,3-DPG concentration is 26-27 mmHg. Human
fetal blood has a P50 of about 19 mm Hg because of
the different chemical structure of fetal hemoglobin.

An increase of 2,3-DPG within the red cell increases

the P50 by about 0.5 mm Hg moH of 2,3-DPG. The
magnitude of the Bohr effect is usually given in terms
of the increase in log P50 per pH unit. The normal
value for human blood is 0.4 at constant PCo2- Note
that although historically the 'Bohr effect' referred to
the change in affinity caused by -Pco2> in modern
usage the term is restricted to the effect of pH. The
temperature effect is 0.24 for the change in log P50
(mmHg^- 1 ).
Much can be learned about the effect of changes in
the oxygen affinity of hemoglobin on the physiology
of high altitude by modeling the oxygen transport
system using computer subroutines for the oxygen
and carbon dioxide dissociation curves (Bencowitz et
al. 1982). Kelman described useful subroutines for
the oxygen dissociation curve (Kelman 1966a,b) and
the carbon dioxide dissociation curve (Kelman
1967). The practical use of these procedures has
been described (West and Wagner 1977). These
procedures are able to accommodate changes in PC02.
pH, temperature and 2,3-DPG concentration, and
allow the investigator to answer questions about the
interactions of these variables which would otherwise be impossibly complicated.

9.3.2

Animals native to high altitude

It has been known for many years that animals that

live at high altitude tend to have an increased oxygen

Figure 9.2 Formation of 2,3-DPG in

erythrocytes. The vertical chain at the left
shows the glycolytic pathway in cells
other than red blood cells. In red cells the
enzyme DPG mutase catalyses the
conversion of much of the 1,3-DPG to
2,3-DPG. (Modified from Mines 1981.)

Oxygen affinity of hemoglobin 111

affinity of their hemoglobin. Figure 6.6 shows part of

the oxygen dissociation curves of the vicuna and
llama which are native to high altitude in the South
American Andes (Hall et al. 1936). The diagram also
shows the range of dissociation curves for eight
lowland animals including humans, horse, dog,
rabbit, pig, peccary, ox and sheep. It can be seen that
the hemoglobin of high altitude native animals has a
substantially increased oxygen affinity. This
adaptation to high altitude is of genetic origin, as is
shown by the fact that a llama brought up in a zoo at
sea level has the same high oxygen affinity.
High altitude birds also show these phenomena.
Hall and his colleagues (1936), during the 1935
International High Altitude Expedition to Chile,
reported that the high altitude ostrich and huallata
have higher oxygen affinities than a group of six
lowland birds including the pigeon, muscovy duck,
domestic goose, domestic duck, Chinese pheasant
and domestic fowl. A particularly interesting
example is the bar-headed goose which is known to
fly over the Himalayan ranges as it migrates between
its breeding grounds in Siberia and its wintering
grounds in India. This remarkable animal has a
blood P50 about 10 mm Hg lower than its close
relatives from moderate altitudes (Black and Tenney
1980).
Deer mice, Peromyscus maniculatus, show the
same relationships. A study was carried out on 10
subspecies that live at altitudes from below sea level
in Death Valley in California to the high mountains
of the nearby Sierra Nevada (4350 m), and it was
found that there was a strong correlation between the
habitat altitude and the oxygen affinity of the blood.
The genetic source of this relationship was proved by
moving one subspecies to another location and
showing that the oxygen affinity was unchanged.
Moreover, the relationship persisted in second
generation animals (Snyder etal 1982).

genetic adaptation. The most familiar to most of us is

the change in amino acid sequence in the globin
chain of hemoglobin in the human fetus. This is also
seen in the bar-headed goose. The next two groups
increase the oxygen affinity of their hemoglobin by
decreasing the concentration of organic phosphates.
This is done with 2,3-DPG in the fetus of the dog,
horse and pig, and by decreasing the concentration
of ATP in the trout and eel.
Some species of tadpoles which frequently live in
stagnant pools have a high oxygen affinity hemoglobin, whereas the adult frogs produce a different
type of hemoglobin with a lower affinity that fits
their higher oxygen environment. Note also that the
tadpole blood shows a smaller Bohr effect. This is
useful because low oxygen and high carbon dioxide
pressures are likely to occur together in stagnant
water, and a large Bohr effect would be disadvantageous because it would decrease the oxygen affinity
of the blood when a high affinity was most needed.
As indicated earlier, the human fetus also has a
high oxygen affinity by virtue of its fetal hemoglobin.
This is essential because the arterial P02 of the fetus is
less than 30 mm Hg. Indeed the human fetus and the
adult climber on the summit of Mount Everest have
some similar features in that in both cases the arterial
P02 is extremely low, and the P50 of the arterial blood
(at the prevailing pH) is also very low (section 9.4.4).
A particularly interesting example of an unusual
human hemoglobin was described by Hebbel et al.
(1978). The authors studied a family in which two of
the siblings had a mutant hemoglobin (AndrewMinneapolis) with a P50 of 17.1 mmHg. They
showed that the siblings with the abnormal hemoglobin tolerated exercise at an altitude of 3100 m
better than the normal siblings.
The last row in Table 6.1 refers to the climber at
extreme altitude who has a marked respiratory
alkalosis which greatly increases the oxygen affinity
of the hemoglobin. This is discussed in detail below.

933
Animals in oxygen deprived
environments

93.4

High altitude is just one of the oxygen deprived

environments in which animals are found, and it is
interesting to consider the variety of strategies that
have been adopted to mitigate the problems posed by
oxygen deficiency. Table 6.1 shows examples of some
of the strategies that have been adopted through

Barcroft et al. (1923) measured the oxygen dissociation curves of three natives of Cerro de Pasco
(4330 m) in Peru at the prevailing Pcc,2 (25-30 mm Hg)
and showed that the curves were displaced to the left,
i.e. there was an increased oxygen affinity. A similar
result was found in acclimatized members of the

High altitude natives

112 Blood gas transport and acid-base balance

expedition. Barcroft (1925) believed that part of the

leftward shift was caused by increased alkalinity of
the blood but part was also due to an intrinsic change
in the affinity of hemoglobin.
During the International High Altitude
Expedition to Chile in 1935, a number of measurements were made on high altitude natives who were
living at 5340 m (PB 401 mm Hg). Some of the men
were accustomed to working each day at 5700 m. The
dissociation curves were found to be within normal
limits for men at sea level, or perhaps shifted slightly
to the right (Keys et al 1936). Measurements were
also made on dilute solutions of hemoglobin taken
both from high altitude residents and from acclimatized lowlanders (Hall 1936). The results were very
similar to those obtained at sea level but the high
altitude residents seemed to have a slightly reduced
oxygen affinity.
Aste-Salazar and Hurtado (1944) measured the
oxygen dissociation curves of 17 healthy Peruvians in
Lima at sea level and 12 other permanent residents of
Morococha (4550 m). These studies were subsequently extended to a total of 40 subjects in Lima
and 30 in Morococha (Hurtado 1964). The mean
value of the P50 at pH 7.4 was 24.7 mm Hg at sea level
and 26.9 mm Hg at high altitude (Figure 9.3). It was

argued that the rightward displacement of the curve

would enhance the unloading of oxygen from the
peripheral capillaries.
More recently Winslow and his colleagues (1981)
reported oxygen dissociation curves on 46 native
Peruvians in Morococha (4550 m, PB 432 mmHg)
and confirmed that at pH 7.4 the P50 was significantly
higher in the high altitude population than in the
sea level controls (31.2 mmHg as opposed to
29.2 mmHg, p < 0.001). However, these investigators also found that the acid-base status of the high
altitude subjects was that of partially compensated
respiratory alkalosis with a mean plasma pH of 7.44.
When the P50 values were corrected to the subjects'
actual plasma pH, the mean value of 30.1 mmHg
could no longer be distinguished from that of the sea
level controls (Figure 9.4). The conclusion was that
the small increase in P50 resulting from the increased

Figure 9.3 Mean positions of the oxygen dissociation curves of

Figure 9.4 Distribution of Pso values at sea level and high

Peruvians in Lima (sea level) and Morococha (4540 m). Note that

altitude. In the top panel, values are expressed at the in vivo pH;

the high altitude natives have a slightly reduced oxygen affinity.

in the bottom at pH 7.4. When corrected for the subjects' plasma

Mean values of the P02 in arterial (A) and mixed venous (V) blood

pH, the in vivo P50 at high altitude falls in the sea level range in all

for the two groups are also shown. (From Hurtado 1964.)

but one subject. (From Winslow et al. 1981.)

Oxygen affinity of hemoglobin 113

concentration of 2,3-DPG in the red cells was offset

by the mild degree of respiratory alkalosis, with the
net result that the position of the oxygen dissociation
curve was essentially the same as that in sea level
controls.
In a controversial study Morpurgo et al. (1976)
reported that Sherpas living permanently at an
altitude of 4000 m in the Nepalese Himalayas had a
substantially increased oxygen affinity at standard
pH. The P50 value of the high altitude Sherpas was
22.6 mmHg, compared with 27.1 mmHg in low
altitude white people. The Sherpa blood was also
reported to have an unusually large Bohr effect.
Interestingly, Sherpas living at low altitude appeared
to have an increased P50 value of 36.7 mm Hg. A
weakness of this study was that the oxygen dissociation curves were determined 5-6 days after the blood
was taken. A subsequent study by Samaja et al.
(1979) failed to confirm these provocative findings.
Samaja et al. also showed that the oxygen affinity
could be completely accounted for by the known
effectors of hemoglobin function: pH, Pcc,2, 2,3-DPG
and temperature.

93*5

Acclimatized lowlanders

As discussed in section 9.2, Barcroft (1911) was

perhaps the first person to measure the position of
the oxygen dissociation curve in acclimatized
lowlanders. This was done at altitudes of 2130 and
3000 m on Tenerife, and he reported that the curve
was shifted to the right if measured at the normal
Pcc,2 of 40 mm Hg, but if the Pcc,2 for those altitudes
was used, the curves had the same position as at sea
level. Barcroft made additional measurements on
Monte Rosa in 1911 (Barcroft et al. 1914) and
reported a slight rightward shift of the curves at the
prevailing PC02. However, during the expedition to
Cerro de Pasco in 1922, a leftward shift was observed
at the prevailing arterial Pcc,2 of 25-30 mmHg
(Barcroft et al. 1923). They made the point that this
might be beneficial because of enhanced oxygen
uptake in the lung owing to the increased oxygen
affinity of the hemoglobin.
During the International High Altitude
Expedition to Chile 1935, three ways of measuring
the oxygen affinity of the hemoglobin were
employed: whole blood at normal pH, whole blood
at the prevailing pH and dilute solutions of hemo-

globin. At constant pH, Keys et al. (1936) reported

that the oxygen affinity of the hemoglobin was
apparently slightly reduced with a change in P50 of
approximately 3.5 mmHg. However, the 'physiological' dissociation curves were displaced to the left
from sea level up to an altitude of approximately
4270 m, though above that they were displaced
increasingly to the right of the sea level positions. On
dilute hemoglobin solutions, Hall (1936) showed
that the oxygen affinity of the hemoglobin was
essentially unchanged compared with sea level.
These somewhat confusing results were substantially clarified when the role of 2,3-DPG in the
red cell was appreciated (Benesch and Benesch 1967,
Chanutin and Curnish 1967). It was shown that this
normal product of red cell metabolism reduced the
oxygen affinity of hemoglobin, and it was then clear
that many previous measurements were unreliable
because of ignorance of this factor. Lenfant and his
colleagues (Lenfant et al 1968, 1969, 1971) showed
that the concentration of 2,3-DPG was increased in
lowlanders when they became acclimatized to high
altitude. The primary cause of the increase in 2,3DPG was the increase in plasma pH above the
normal sea level value as a result of the respiratory
alkalosis. When subjects were made acidotic with
acetazolamide there was no increase in plasma pH or
red cell 2,3-DPG concentration at high altitude, and
the oxygen dissociation curve did not shift to the
right. It was argued that the increase in 2,3-DPG was
an important feature of the acclimatization process
of lowlanders and of the adaptation to high altitude
of highlanders (Lenfant and Sullivan 1971).
Subsequent measurements on lowlanders at high
altitude have confirmed these changes, although
there is still some uncertainty about whether acclimatized lowlanders develop complete metabolic
compensation for their respiratory alkalosis (that is,
whether the pH returns to 7.4). Certainly this does
not happen at extremely high altitudes. During the
1981 American Medical Research Expedition to
Everest, Winslow et al. (1984) made an extensive
series of measurements on acclimatized lowlanders
at an altitude of 6300 m. They also obtained data on
two subjects who reached the summit (8848 m).
These measurements were made on venous blood
samples taken at an altitude of 8050 m the morning
after the summit climb. Winslow and his colleagues
found that the red cell concentration of 2,3-DPG
increased with altitude (Figure 9.5) and that this was

114 Blood gas transport and acid-base balance

These differences can probably be explained by the

smaller degree of acclimatization because of the
limited time available in the low pressure chamber.

9.3.6 Physiological effects of changes

in oxygen affinity

Figure 9.5 Blood variables measured on the 1981 American

Medical Research Expedition to Everest at sea level, 6300 m, 8050 m
and 8848 m (summit). pHb, pH blood. (From Winslow et al. 1984.)

associated with a slightly increased P50 value when

expressed at pH 7.4. However, because the respiratory alkalosis was not fully compensated, the subjects' in vivo P50 at 6300 m (27.6 mm Hg) was slightly
less than at sea level (28.1 mm Hg). The estimated in
vivo P50 was found to become progressively lower at
8050 m (24.9 mm Hg), and on the summit at 8848 m
it was as low as 19.4 mm Hg in one subject. Thus
these data show that, at extreme altitudes, the blood
oxygen dissociation curve shifts progressively leftward (increased oxygen affinity of hemoglobin) primarily because of the respiratory alkalosis. Indeed
this effect completely overwhelms the relatively small
tendency for the curve to shift to the right because of
the increase in red cell 2,3-DPG.
The results obtained on Operation Everest II were
generally in agreement with these (Sutton et al. 1988)
except that the PC02 values at extreme altitude were
higher, and the blood pH values therefore lower.

As indicated above, there have been differences of

opinion on whether a decreased or an increased
oxygen affinity is beneficial at high altitude. Barcroft
et al. (1923) found a slightly increased affinity and
argued that this would enhance oxygen loading in
the lung. However, Aste-Salazar and Hurtado (1944)
reported a slight decrease in oxygen affinity in high
altitude natives at Morococha and reasoned that this
would enhance oxygen unloading in peripheral
capillaries. The same argument was used by Lenfant
and Sullivan (1971) when the influence of the
increased red cell concentration of 2,3-DPG on the
oxygen dissociation curve was appreciated. They
stated that the decreased oxygen affinity would help
the peripheral unloading of oxygen, and that this was
one of the many features both of acclimatization of
lowlanders to high altitude and of the genetic
adaptation of highlanders.
However, there is now strong evidence that an
increased oxygen affinity (left-shifted oxygen
dissociation curve) is beneficial, especially at higher
altitudes, and particularly on exercise (Bencowitz et
al. 1982). Indeed this should not come as a surprise
when it is appreciated that many animals increase the
oxygen affinity of their blood in oxygen-deprived
environments by a variety of strategies (section 9.3.3;
Table 6.1). In addition, Eaton et al. (1974) reported
that rats whose oxygen dissociation curve had been
left-shifted by cyanate administration showed an
increased survival when they were decompressed to a
barometric pressure of 233 mm Hg. The controls
were rats with a normal oxygen affinity. Turek et al.
(1978) also studied cyanate-treated rats and found
that they maintained better oxygen transfer to tissues
during severe hypoxia than normal animals. In
addition, we have already referred to the studies of
Hebbel et al (1978) who found a family with two
members who had a hemoglobin with a very high
affinity (Hb Andrew-Minneapolis, P50 17.1 mm Hg).
These two members performed better during
exercise at an altitude of 3100 m than two siblings
with normal blood.

Oxygen affinity of hemoglobin 115

Theoretical studies show that a high oxygen

affinity is beneficial at high altitude, especially on
exercise (Tureketa/. 1973, Bencowitz et al. 1982). In
one study, oxygen transfer from air to tissues was
modeled for a variety of altitudes and a range of
oxygen uptakes (Bencowitz et al. 1982). The oxygen dissociation curve was shifted both to the left
and right with P50 of 16.8 mmHg (left-shifted),
26.8 mmHg (normal) and 36.8 mmHg (rightshifted). The pulmonary diffusing capacity for
oxygen was varied over a wide range and all the
determinants of oxygen transport, including
temperature, base excess, hemoglobin concentration
and hematocrit, were taken into account.
The results showed that in the presence of
diffusion limitation of oxygen transfer across the
blood-gas barrier in the lung, a left-shifted curve
resulted in the highest P02 of mixed venous blood

(which was taken as an index of tissue P0z) (Figure

9.6). In other words, in the presence of diffusion
limitation, an increased oxygen affinity of hemoglobin results in a higher tissue P02. The explanation
is that the increased affinity enhances the loading of
oxygen in the lung more than it interferes with
unloading in peripheral capillaries. This appears to
be the physiological justification for the increased
oxygen affinity so frequently seen among animals
that live in low oxygen environments (Table 6.1).
The role of an increased oxygen affinity is seen
dramatically in a climber on the summit of
Mount Everest. Despite some increase of 2,3-DPG
concentration within the red cell, the extremely low
PC02 of 7-8 mmHg as a result of the enormous
increase in ventilation causes a dramatic degree of
respiratory alkalosis with an arterial pH calculated to
exceed 7.7 (West et al. 1983b). As a result, the in vivo

Figure 9.6 Results of a theoretical study

showing changes in calculated arterial and
mixed venous P02 with increasing oxygen
uptake at four altitudes for three values of
P50. The P50 values are normal (N,
26.8 mm Hg), right-shifted (R, 36.8 mm Hg),
and left-shifted (L, 16.8 mm Hg). The
nearly horizontal lines labeled 'mixed
venous'show the P02 values for an
infinitely high pulmonary oxygen diffusing
capacity. The curved lines peeling away
from these lines show the results of
diffusion limitation. In this example, the
diffusing capacity of the membrane for
oxygen (DM02) is 80 mL mirr1 mm Hg~1.
Note that at the highest level of exercise,
and especially at high altitude, the leftshifted curve gives the highest values of P02
in mixed venous blood and therefore the
tissues. (From Bencowitz et al. 1982.)

116 Blood gas transport and acid-base balance

P50 is about 19 mm Hg, which is very similar to that

of the human fetus in utero. The resulting striking
increase in oxygen affinity of hemoglobin plays a
major role in allowing the climber to survive this
extremely hypoxic environment (Chapter 12).

9.4
9.4.1

ACID-BASE BALANCE
Introduction

This topic overlaps with that of the previous section,

oxygen affinity of hemoglobin, because the affinity at
high altitude is primarily determined by the pH of
the blood together with the concentration of 2,3DPG in the red cells. However, for convenience,
available information on acid-base status is set out
here.

9*4*2

During acclimatization

When a lowlander goes to high altitude, hyperventilation occurs as a result of stimulation of the
peripheral chemoreceptors by the hypoxemia
(Chapter 4), the arterial PC02 falls, and the arterial pH
rises in accordance with the Henderson-Hasselbalch
equation:

where [HCO3] is the bicarbonate concentration in

millimoles per liter and the PC02 is in mm Hg.
However, the kidney responds by eliminating
bicarbonate ion, being prompted to do this by the
decreased PC02 in the renal tubular cells. The result
is a more alkaline urine because of decreased
reabsorption of bicarbonate ions. The resulting
decrease in plasma bicarbonate then moves the
bicarbonate/PCO2 ratio back towards its normal level.
This is known as metabolic compensation for the
respiratory alkalosis. The compensation may be
complete, in which case the arterial pH returns to
7.4 or, more usually, incomplete with a steady-state
pH that exceeds 7.4.
The time course of the changes in arterial pH
when normal subjects are taken abruptly to high
altitude has been studied by several investigators
(Severinghaus et al. 1963, Lenfant et al. 1971,

Dempsey et al. 1978). In one study, lowlanders were

taken from sea level to an altitude of 4509 m (PB
446 mm Hg) in less than 5 h, and remained there for
4 days. The arterial pH rose to a mean of about 7.47
within 24 h and then apparently slowly declined but
was still about 7.45 at the end of the 4-day period. On
return to sea level the pH fell steadily to reach the
normal value of 7.4 after about 48 h (Lenfant et al.
1971).
In another study, four normal subjects were taken
abruptly to 3800 m for 8 days. The arterial pH rapidly
rose from a mean of 7.424 at sea level to 7.485 after
2 days, and remained essentially constant, being
7.484 at the end of 8 days (Severinghaus et al 1963).
In a further study, 11 lowlanders moved to 3200 m
altitude where they remained for 10 days (Dempsey
et al 1978). The arterial pH rose by 0.03 to 0.04 units
within 2 days and then remained essentially
unchanged. In all instances, the arterial PC02 continued to fall as did the plasma bicarbonate concentration. However, it appears that the return of the
arterial pH to (or near to) its sea level value is very
slow.

9*43

High altitude natives

Most authors have reported a fully compensated

respiratory alkalosis in high altitude natives with
arterial pH values close to 7.4. Table 9.1 shows a
summary of a number of published papers prepared
by Winslow and Monge (1987). This is perhaps the
expected finding. The body generally maintains the
arterial pH within very narrow limits in health, and it
seems reasonable that people who are born and live
at high altitude would fully compensate for their
reduced Pcc,2 by eliminating bicarbonate and
restoring the pH to the normal sea level value.
However, Winslow et al (1981) measured the
arterial pH in 46 high altitude natives of Morococha
(4550 m, PB 432 mm Hg) and reported that the mean
plasma pH was 7.439 0.065. In other words these
highlanders did not have a fully compensated
respiratory alkalosis but their blood lay slightly on
the alkaline side of normal. As pointed out in section
9.3.4, the result of this mild respiratory alkalosis was
to restore the oxygen dissociation curve to the
normal sea level position because there was an
increase in red cell 2,3-DPG concentration which
tended to move the curve to the right.

Acid-base balance 117

Table 9.1 Blood-gas and pH values in high altitude natives

4300
4300
4500
4515
4300
4300
3700
4545
4820
3960
4880
4500
4500
4300
4500
4300
4500

3
12
40
22
6
5

3
4
6
10
6
4
4
35

20.6a
19.5a
56.0
73.8

73.4
65.5
54.4
63.3

61.0

46.7

45.1

45.2
44.1
50.8
51.7

84.6

80.1
82.8

74.7
73.3

85.7

33.3
33.8
32.5
39.0
3.0

31.6
32.2
32.9
34.0

7.360
7.370
7.400
7.431 b
7.429b
7.431b
7.424b
7.426b
7.399

7.414
7.405
7.405
7.395

Barcroftrto/. (1923)
Aste-Salazar and Hurtado (1944)
Hurtadorto/. (1956)
Chiodi (1957)
Mongeef al. (1964)
Monger al. (1964)
Mongeef al. (1964)
Mongeefo/. (1964)
Mongeefo/. (1964)
Lahmetal. (1967)
Lahmetal. (1967)
Lenfantefo/. (1969)
Lenfantdtfo/. (1969)
Torrance(1970)c
Torrance(1970)c
Rennie(1971)
Winslowrtfl/. (1981)

See Winslow and Monge (1987) for details and sources.

-, no data available.
a
Hemoglobin concentration (g dL~1).
b
Plasma pH.
c
Himalayan subjects.

The interpretation of these results is complicated

by the fact that Winslow et al. (1981) believed that
the increased red cell concentration that is seen at
high altitude had an effect on the glass electrode for
measuring pH (Whittembury et al 1968). If the
observed pH is corrected for this effect of increased
red cell concentration, the calculated plasma pH
becomes 7.395, as shown in the bottom row of Table
9.1. However, no other investigators have corrected
the pH in this way and the conclusion from the work
of Winslow and his colleagues is that high altitude
natives have a mildly uncompensated respiratory
alkalosis with an arterial pH that exceeds 7.4.

9.4.4

Acclimatized lowlanders

When sufficient time is allowed for extended

acclimatization to high altitude, the arterial pH
returns close to the normal value of 7.4, at least up to
altitudes of 3000 m. For example, during the 1935
International High Altitude Expedition to Chile, Dill
and his colleagues (1937) found that the arterial pH
increased little if at all up to this altitude, but above

3000 m higher values of pH were found, with a mean

of about 7.45 at an altitude of 5340 m. A few
measurements on acclimatized subjects at an altitude
of 5800 m during the 1960-1 Himalayan Scientific
and Mountaineering Expedition indicated values of
between 7.41 and 7.46 (West et al. 1962).
Extensive measurements were made by Winslow
et al. (1984) during the 1981 American Medical
Research Expedition to Everest. The mean arterial
pH of acclimatized lowlanders living at an altitude of
6300 m was 7.47 (Figure 9.7). It was also possible to
calculate the arterial pH at an altitude of 8050 m
(Camp 5) and the Everest summit (8848 m). The
calculations were made from the base excess
measured on venous blood samples taken at 8050 m
and measurements of alveolar PC02 on sealed samples
of alveolar gas brought back to the USA. It was
assumed that the arterial and alveolar PC02 values
were the same, and also that base excess did not
change over the 24 h between the summit and Camp
5. As discussed in section 9.4.5, there is evidence that
base excess was changing very slowly at this great
altitude. The mean arterial pH of two climbers at
8050 m was 7.55, and the one subject whose alveolar

118 Blood gas transport and acid-base balance

Figure 9.7 Davenport diagram showing the pH, PC02 and plasma
bicarbonate concentration of arterial blood during the 1981
American Medical Research Expedition to Everest at altitudes of
6300 m, 8050 m and 8848 m (summit). Note the increasingly
severe respiratory alkalosis at the extreme altitudes. The points for
8050 and 8848 m are from Pizzo. (Data from Winslow et al. 1984.)

PC02 was measured as 7.5 mm Hg on the summit gave

a calculated arterial pH of over 7.7.
These climbers were not 'acclimatized' to 8050 or
8848 m in the sense that they had spent long periods
at these great altitudes. However, it is not possible to
spend an extended time at an altitude such as 8000 m
because high altitude deterioration occurs so rapidly.
Thus the values probably represent the inevitable
respiratory alkalosis which occurs in climbers who go
so high.

9*4*5 Metabolic compensation for

respiratory alkalosis
An interesting feature of the studies at extreme
altitude referred to above is that metabolic compensation for the respiratory alkalosis appears to be
extremely slow. The mean base excess measured on
three subjects who were living at an altitude of 6300 m
was -7.9 mmol L"1. The measurements made on
venous blood taken from two climbers at 8050 m gave
a mean value of-7.2 mmol Ir1, essentially the same.
The 8050 m measurements were taken several days
after the climbers had left Camp 2 at 6300 m, and the

data therefore suggest that metabolic compensation

was proceeding extremely slowly despite the fact that
the PC02 had fallen considerably. For example, the
mean PC02 at 6300 m was 18.4 mmHg, at 8050 m
11.0 mmHg, and at 8848 m (summit) 7.5 mmHg.
The last value was obtained from only one subject.
The reason for the very slow change in bicarbonate
concentration at these great altitudes is unclear. One
possible factor is chronic dehydration. Blume et al.
(1984) measured serum osmolality at sea level,
5400 m and 6300 m in 13 subjects of the expedition
and showed that the mean value rose from 290
1 mmol kg~! at sea level to 295 2 at 5400 m, and to
302 4 at 6300 m. This volume depletion occurred
despite adequate fluids to drink and a reasonably
normal lifestyle. An interesting feature of the fluid
balance studies was that plasma arginine vasopressin
(AVP) concentrations remained unchanged from sea
level to 6300 m despite the hyperosmolality. A possible factor in the volume depletion was the large
insensible loss of fluid at these great altitudes as a
result of hyperventilation. However, the failure of the
vasopressin levels to change suggests that there is
some abnormality of body fluid regulation.
It is known that the kidney is slow to correct an
alkalosis in the presence of volume depletion. It
appears that when given the option of correcting
fluid balance or correcting acid-base balance, the
kidney gives a higher priority to fluid balance. In
order to correct the respiratory alkalosis, bicarbonate
ion excretion must be increased (or reabsorption
decreased) and this entails the loss of a cation which
inevitably aggravates the hyperosmolality. This
would explain the reluctance of the kidney to correct
a respiratory alkalosis in the presence of volume
depletion.
A different explanation was offered by Gonzalez et
al. (1990) when they studied the slow metabolic
compensation of respiratory alkalosis in a chronically hypoxic rat model. They found that the rate of
metabolic compensation was indeed slower than in
acute hypoxia, and they attributed this to the lower
plasma bicarbonate concentration resulting from
chronic hypoxia. They argued that, because proton
secretion and reabsorption of bicarbonate are
functions of the bicarbonate load offered to the renal
proximal tubule, it is probable that the slower
increase in bicarbonate excretion of the chronically
hypoxic animals was ultimately the result of the
lower plasma bicarbonate concentration.

10
Peripheral tissues
10.1
10.2
10.3
10.4

Introduction
Historical
Diffusion in peripheral tissues
Capillary density

119
120
121
123

10.5
10.6
10.7
10.8

Muscle fiber size

Volume of mitochondria
Myoglobin concentration
Intracellular enzymes

125
125
126
127

SUMMARY

10.1

INTRODUCTION

The movement of oxygen from the peripheral capillaries to the mitochondria is the final link in the oxygen cascade. In muscle cells, the diffusion of oxygen
may be facilitated by the presence of myoglobin, and
it is possible that some convection also occurs in the
cytoplasm of some cells. There is good evidence that
the P02 in the immediate vicinity of the mitochondria
of many cells is very low, of the order of 1 mm Hg.
Many investigators believe that much of the pressure
drop from the capillary to the mitochondria occurs
very close to the capillary wall because of the limited
surface area available for diffusion. This leads to the
conclusion that the diffusion distance from the capillary wall to the mitochondria is relatively unimportant as a barrier to oxygen transport. This diffusion
distance is decreased at high altitude, mainly because
of the reduction in diameter of the muscle fibers.
There is also an increase in myoglobin concentration
and mitochondrial density at moderate altitudes. At
extreme altitudes, mitochondrial volume in human
skeletal muscle is decreased. Increases in the concentration of oxidative enzymes are seen at moderate
altitudes, as is the case following training at sea level.
The reverse occurs at extreme altitudes, where oxidative enzymes are decreased.

The diffusion of oxygen from the peripheral capillaries to the mitochondria, and its consequent utilization by these organelles, constitutes the final link of
the oxygen cascade which begins with the inspiration
of air. Despite its critical importance, many uncertainties remain concerning the changes that occur in
peripheral tissues both in acclimatized lowlanders
and in the adaptation of high altitude natives. An
obvious reason for this paucity of knowledge is the
difficulty of studying peripheral tissues in intact
humans. Much of our information necessarily comes
from measurements on experimental animals
exposed to low barometric pressures, though some
additional studies have been made on tissue biopsies
in humans.
It is probable that tissue factors play a very important role in the remarkable tolerance of high altitude
natives to exercise at high altitude. As was pointed
out in Chapter 5, people born at high altitude often
have a reduced ('blunted') ventilatory response to
hypoxia. At first sight this is counterproductive
because it will result in a lower alveolar P02, and
therefore a lower arterial P02> other things being
equal. However, Samaja et al. (1997) found that the
arterial P02 and oxygen saturation (estimated from

120 Peripheral tissues

earlobe blood) were the same in a group of

Caucasians and Sherpas at altitudes of 3400m,
5050 m and 6450 m, despite the fact that the Sherpas
had a higher arterial -PCo2- This suggests an improved
efficiency of oxygen transfer in the lung, and may be
linked to the higher pulmonary diffusing capacity of
high altitude natives. However, even if the arterial
P02 is the same in highlanders as lowlanders, the better exercise performance of the former at high altitude suggests that there are important adaptations
within the tissues of which we are so far ignorant.
The present chapter overlaps with others to some
extent. The principles of diffusion of gases through
tissues were dealt with in Chapter 6, and there is a
discussion in Chapter 11 of how diffusion limitation
in peripheral tissues may limit oxygen delivery during exercise. This topic is also alluded to in Chapter
12 in the discussion of limiting factors at extreme
altitudes.

10.2

HISTORICAL

Early physiologists interested in high altitude did not

attach much importance to tissue changes. For
example, Paul Bert in La Pression Barometrique
hardly refers to the possibility of tissue acclimatization, although he deals at some length with changes
in respiration and circulation. At one point he wonders whether the metabolism of high altitude natives
is different from that of lowlanders:
... just as a Basque mountaineer furnished with a
piece of bread and a few onions makes expeditions
which require of the member of the Alpine Club
who accompanies him the absorption of a pound of
meat, so it may be that the dwellers in high places
finally lessen the consumption of oxygen in their
organism, while keeping at their disposal the same
quantity of vital force, either for the equilibrium of
temperature, or the production of work. Thus we
could explain the acclimatization of individuals, of
generations, of races. (Bert 1878, p. 1004 in the
1943 translation)

Incidentally, we now know that the oxygen

requirements of a given amount of work are no different at high altitude compared with sea level, or in
high altitude natives compared with lowlanders. Bert
goes on,

But we should consider not only the acts of nutrition, but also the stimulation, perhaps less, which
an insufficiently oxygenated blood causes in the
muscles, the nerves, and the nervous centers....

However, he does not carry his speculations any

further.
There is a delightful section where Bert suggests that
there may be changes in the blood at high altitude:
We might ask first whether, by a harmonious compensation of which general natural history gives us
many examples, either by a modification in the
nature or the quantity of hemoglobin or by an
increase in the number of red corpuscles, his blood
has become qualified to absorb more oxygen under
the same volume, and thus to return to the usual
standard of the seashore (Bert 1878, p. 1000 in the
1943 translation).

He goes on to say that this hypothesis would be very

easy to test. Since it had recently been shown:
that the capacity of the blood to absorb oxygen
does not change after putrefaction, nothing would
be easier than to collect the venous blood of a
healthy vigorous man (an acclimated European or
an Indian) or of an animal, defibrinate it, and send
it in a well-corked flask; it would then be sufficient
to shake it vigorously in the air to judge its capacity
of absorption during life (Bert 1878, p. 1008 in the
1943 translation).

This beautiful research project handed to the

research community on a silver plate was taken up by
Viault (1890) with exactly the results predicted by
Bert. However, this project studied a change in the
blood compartment of the body rather than in the
peripheral tissues with which this chapter is chiefly
concerned.
Following the work of Krogh (1919, 1929) on the
increase in the number of open capillaries in muscle
when the oxygen demands were raised by exercise, it
was natural to wonder whether increased capillarization was a feature of tissue acclimatization in
response to chronic hypoxia. It was subsequently
reported that capillaries in the brain, heart and liver
were significantly dilated and that their number was
apparently increased after hypoxic exposure
(Mercker and Schneider 1949, Opitz 1951). As we
shall see later, some more recent measurements confirm these findings. However, other studies show that

Diffusion in peripheral tissues 121

in some situations the actual number of capillaries in

muscle tissue does not increase as a result of chronic
hypoxia, but the intercapillary diffusion distance
lessens because the muscle fibers become smaller.
Hurtado and his co-workers (1937) reported an
increase in the intracellular concentration of the
oxygen-carrying pigment, myoglobin, in high
altitude animals. The measurements were made on
dogs born and raised in Morococha (4550 m) and
the increased concentrations were found in the
diaphragm, myocardium and muscles of the chest
wall and leg. The controls were dogs from Lima at sea
level. Since then a number of other investigators have
reported increased tissue myoglobin levels at high
altitude.
An increase in mitochondrial density was shown in
the myocardium of cattle born and raised at high altitude by Ou and Tenney (1970). Changes in mitochondrial enzymes in muscle of high altitude natives
were reported by Reynafarje (1962). He found alterations in the enzyme systems NADH-oxidase,
NADPH-cytochrome c-reductase, NAD[P] + transhydrogenase and others. These measurements were
made on muscle biopsies taken from permanent residents of Cerro de Pasco in Peru at an altitude of
4400 m. The sea level controls were residents of Lima.

103
DIFFUSION IN PERIPHERAL
TISSUES

10.3.1

oxygen consumption of the muscle increases, additional capillaries open up, thus reducing the diffusion distance and increasing the capillary surface area
available for diffusion. As discussed in section 6.3.2,
carbon dioxide diffuses about 20 times faster than
oxygen through tissues because of its much higher
solubility, and therefore the elimination of carbon
dioxide poses less of a problem than oxygen delivery.
Early workers believed that the movement of oxygen through tissues was by simple passive diffusion.
However, it is now believed that facilitated diffusion
of oxygen probably occurs in muscle cells as a result
of the presence of myoglobin. This heme-protein has
a structure which resembles hemoglobin but the dissociation curve is a hyperbola, as opposed to the Sshape of the oxygen dissociation curve of whole
blood (Figure 10.1). Another major difference is that
myoglobin takes up oxygen at a much lower P02 than
hemoglobin, that is, it has a very low P50 of about
5 mm Hg. This is a necessary property if the myoglobin is to be of any use in muscle cells where the
tissue P02 is very low. Scholander (1960) and
Wittenberg (1959) have shown experimentally that
myoglobin can facilitate oxygen diffusion.
Other modes of oxygen transport are possible
within cells. Streaming movements of cytoplasm
have been observed and it is conceivable that such
movements, known as 'stirring', enhance the
transport of oxygen by convection. Another hypothesis is that oxygen moves into some cells along

Principles

Oxygen moves from the peripheral capillaries to the

mitochondria, and carbon dioxide moves in the
opposite direction by the process of diffusion. Pick's
law of diffusion was discussed in section 6.3.2. It
states that the rate of transfer of a gas through a sheet
of tissue is proportional to the area of the tissue and
to the difference in gas partial pressure between the
two sides, and inversely proportional to the tissue
thickness.
In discussing the lung, it was pointed out that the
blood-gas barrier of the human lung is extremely
thin, being only 0.2-0.3 (im in many places. By contrast, the diffusion distances in peripheral tissues are
typically much greater. For example, the distance
between open capillaries in resting muscle is of the
order of 50 u,m. However, during exercise, when the

Figure 10.1 Comparison of the oxygen dissociation curves for

normal human blood (curve A) and myoglobin (curve B). The P50
values are approximately 27 and 5 mm Hg respectively. (From
Roughton 1964.)

122 Peripheral tissues

invaginations of the lipid cell membrane in which it

has a high solubility (Longmuir and Betts 1987).
There is good evidence that the P02 in the immediate vicinity of the mitochondria is very low, being of
the order of 1 mm Hg. In fact many models of oxygen transfer in tissues assume that the mitochondrial
P02 is so low that it can be neglected in the context of
the P02 of the capillary blood, which is of the order of
30-50 mm Hg. In measurements of suspensions of
liver mitochondria in vitro, oxygen consumption has
been shown to continue at the same rate until the P02
of the surrounding fluid falls to the region of
3 mm Hg. Measurements of P02 at the sites of oxygen
utilization based on the spectral characteristics of
cytochromes also indicate that the P02 is probably
less than 1 mmHg (Chance 1957, Chance et al.
1962). Thus it appears that the purpose of the much
higher P02 of capillary blood is to ensure an adequate
pressure for diffusion of oxygen to the mitochondria
and that, at the actual sites of oxygen utilization, the
P02 is extremely low.

Figure 10.2 Fall in ?0i between adjacent capillaries. In (a) three

hypothetical cylinders of tissue are shown and oxygen is diffusing
into these cylinders from capillaries at the periphery. In (2) the
cylinder had a critical radius (Rj, and in (3) the radius of the
cylinder is so large that there is an anoxic zone in the middle of
the cylinder, (b) shows a section along the hypothetical cylinder of

103.2

Tissue partial pressures

tissue. The P02 in the blood adjacent to the tissue is assumed to fall
from 100 to 20 mm Hg along the capillary. Lines of equal P02 are

A classical model to analyze the distribution of P02

values in tissue was described by August Krogh
(1919). He considered a hypothetical cylinder of tissue around a straight, thin capillary into which blood
entered with a known P02. As oxygen diffuses away
from the capillary, oxygen is consumed by the tissue
and the P02 falls. If' simplifying assumptions are
made, such as uniform consumption rate of oxygen
in every part of the tissue, an equation can be written
to describe the P02 profile (Krogh 1919, Piiper and
Scheid 1986).
Another model is shown in Figure 10.2 (Hill
1928). In (a) we see a cylinder of tissue which is supplied with oxygen by capillaries at its periphery: in
(1) the balance between oxygen consumption and
delivery (determined by the capillary P02, the intercapillary distance Rc, and the oxygen consumption
rate of the tissue) results in an adequate P02 throughout the cylinder; in (2) the intercapillary distance or
the oxygen consumption has been increased until the
P02 at one point in the tissue falls to zero. This is
referred to as a critical situation. In (3) there is an
anoxic region where aerobic (that is, oxygenutilizing) metabolism is impossible. Under anoxic
conditions the tissue energy requirements must be

shown. Note the possibility of a 'lethal corner' in the middle of the

cylinder at the venous end. (From West 1985.)

met by obligatory anaerobic glycolysis with the consequent formation of lactic acid.
The situation along the tissue cylinder is shown in
(b). It is assumed that the P02 in the capillaries at the
periphery of the tissue cylinder falls from 100 to
20 mmHg as shown from left to right. As a consequence the P02 in the center of the tissue cylinder
falls towards the venous end of the capillary. It is
clear that, on the basis of this model, the most vulnerable tissue is that furthest from the capillary at its
downstream end. This was referred to as the 'lethal
corner'. It is possible that this pattern of focal anoxia
is responsible for some tissue damage at high altitude. For example, it may explain how some nerve
cells of the brain are damaged at great altitudes causing the residual impairment of central nervous
system function. This is discussed in Chapter 16.
The concept of a cylinder of tissue surrounded by
a network of capillaries is supported by studies
emphasizing the tortuosity of capillaries around
skeletal muscle cells (Potter and Groom 1983,
Mathieu-Costello 1987). Although in many histolog-

Capillary density 123

ical sections the capillaries of skeletal muscle appear

at first sight to run chiefly parallel to the muscle
fibers, this is an oversimplification because of the
connections between adjacent capillaries and also the
tortuosity, which increases considerably as a result of
muscle shortening (Mathieu-Costello 1987). Thus a
reasonable model of oxygen delivery to muscle is a
syncytium of capillaries surrounding a tubular muscle cell.
Recent studies by Honig and his associates (1991)
have indicated that the P0l profiles shown in Figure
10.2 may be misleading in skeletal muscle. These
investigators rapidly froze working muscles of experimental animals and then measured the degree of
oxygen saturation of the intracellular myoglobin
using a spectrometer with a narrow light beam. The
intracellular P02 was inferred from the myoglobin
oxygen saturation. These data and theoretical work
by the same group suggest that the major resistance
to oxygen diffusion from capillary to muscle fiber
mitochondria is at the capillary-fiber interface, i.e.
the thin carrier-free region including plasma,
endothelium and interstitium. This in turn necessitates a large driving force (P02 difference) at that site
to deliver oxygen to the muscle fibers. Some of the
theoretical results of this group are shown in Figure
10.3 where it can be seen that most of the fall of P02
apparently occurs in the immediate vicinity of the
peripheral capillary and that, throughout the muscle
cell, the P02 is remarkably uniform and very low (of
the order of 1-3 mm Hg). This pattern results chiefly
from the presence of myoglobin which facilitates the
diffusion of oxygen within the muscle fibers.

10,4

CAPILLARY DENSITY

One way to improve tissue diffusion under conditions of oxygen deprivation such as high altitude is to
reduce the intercapillary distance. The technical
name for the number of capillaries per unit volume
of tissue is capillary density. It has been known since
the time of Krogh (1919) that the number of open
capillaries in a muscle depends on the degree of
metabolic activity. During exercise additional capillaries open up, thus reducing the diffusing distance
and increasing the diffusing surface area. Exercise
training is known to increase the number of capillaries in skeletal muscle (Saltin and Gollnick 1983).

Figure 10.3 Calculated distribution of P02 around three

capillaries in a heavily working red fiber of skeletal muscle. P02
contours are at intervals of 1 mm Hg. There is a rapid fall of P02 in
the immediate vicinity of the capillary, and within the muscle cell
the P02 is relatively uniform and very low. (From Honig et al.
1991.)

Early studies apparently showed increased vascularization of the brain, retina, skeletal muscle and
liver of experimental animals exposed to low barometric pressures over several weeks (Mercker and
Schneider 1949, Opitz 1951, Valdivia 1958, Cassin et
al. 1971). Tenney and Ou (1970) measured the rate
of loss of carbon monoxide from subcutaneous gas
pockets in rats after 3 weeks of simulated exposure to
5600 m and concluded that there was a 50 per cent
increase in capillary number.
However, some of these studies were questioned
by Banchero (1982) who argued that the results
obtained by Valdivia (1958) and Cassin et al. (1971)
might be influenced by technical errors. Many investigators now believe that, although capillary density
increases in skeletal muscles with exposure to high
altitude, this is generally not caused by the formation
of new capillaries, but by a reduction in size of the
muscle fibers. This result has been found in guinea-

124 Peripheral tissues

pigs (Figure 10.4) which were studied at sea level, in

Denver at 1610 m, at 3900 m (in a species native to
the Andes) and at a simulated altitude of 5100 m
(Banchero 1982).
The same pattern has been described in acclimatized humans where muscle samples were obtained
by biopsy. For example, Cerretelli and his co-workers
obtained muscle biopsies on climbers immediately
after they had spent several weeks attempting to
climb Lhotse Shar (8398 m) in Nepal and showed
that, although the capillary density was somewhat
raised, the increase could be wholly accounted for by
a reduction of muscle fiber size (Boutellier et al.
1983, Cerretelli et al. 1984). A similar result was
found in Operation Everest II in six volunteers who

Figure 10.4 Data showing capillary density (number of

capillaries per square millimeter of cross-section) and
capillary/fiber ratio (number of capillaries per muscle fiber) in
gastrocnemius muscle of four groups of guinea-pigs. These were
studied at sea level, in Denver at 1610 m, at 3900 m (Andean
natives) and at simulated altitude of 5100 m. The data are
consistent with the increase in capillary/fiber ratio being explained
by a decrease in cross-sectional area of the muscle fibers. (From
Banchero 1982.)

were gradually decompressed to the simulated altitude of Mount Everest over a period of 40 days.
Needle biopsies from the vastus lateralis showed a
significant (25 per cent) decrease in cross-sectional
area of type I fibers, and a 26 per cent decrease (nonsignificant) for type II fibers. Capillary to fiber ratios
were unchanged and there was a trend (nonsignificant) towards an increase in capillary density
(MacDougall et al. 1991).
In contrast to the studies showing that new capillaries in skeletal muscle do not develop as a result of
exposure to high altitude, some recent reports do
find increased capillarization. For example, MathieuCostello et al. (1998) reported increases in the number of capillaries in flight muscles of finches at high
altitude, and increased capillarity was also found in
leg muscles of finches living at high altitude (Hepple
et al. 1998). These investigators believe that whether
increased capillary number (and mitochondrial density) occur at high altitude depends on the level of
metabolic stress on the muscle, and this links with
the issue of training at altitude where similar changes
are seen.
Although many studies show that the number of
new capillaries in skeletal muscle does not increase as
a result of exposure to prolonged hypoxia, it has been
suggested that there are changes in the configuration
of the capillaries with increased tortuosity that would
effectively increase capillary surface area and
enhance gas diffusion (Appell 1978). However, this
result has not been confirmed by Mathieu-Costello
and Poole (Mathieu-Costello 1989, Poole and
Mathieu-Costello 1990), who showed that muscle
capillary tortuosity does not increase with chronic
exposure to hypoxia when account is taken of sarcomere length. These investigators believe that Appell's
results may be explained by failure to control the
state of contraction of the muscle. It is known that
the degree of capillary tortuosity increases during
muscle shortening (Mathieu-Costello 1987).
This lack of increase in the number of capillaries
per muscle fiber at high altitude found in some studies should be contrasted with the increase in muscle
capillarity which occurs with training. Longitudinal
studies in humans have shown that exercise training
increases muscle capillarity including both the capillary/fiber ratio and number of capillaries per square
millimeter within several weeks (Andersen and
Henricksson 1977, Brodal et al. 1977, Ingjer and
Brodal 1978). Furthermore, it has been demon-

Volume of mitochondria 125

Table 10.1 Comparison of tissue changes caused by training and those associated with exposure to high altitude

Capillary density in skeletal muscle

Increased due to new capillaries

Increased due to reduction in diameter

of muscle fibers

Fiber diameter of skeletal muscle

May be increased

Decreased

Myoglobin concentration

No change in humans

Increased in skeletal, heart muscle

Muscle enzymes

No change in glycolytic,
increase in oxidative

Similar changes at moderate altitudes; at

extreme altitudes, increase in glycolytic
and decrease in oxidative

Mitochondria

Increased volume density

Increased volume density in some

animals at moderate altitude but
reduced density in humans at extreme
altitude
Different intracellular distribution, e.g.
loss of subsarcolemmal mitochondria in
comparison to training

strated that the increased capillary supply is proportional to the increased maximum oxygen uptake
(Andersen and Henricksson 1977). The increase in
capillaries is found in all fiber types provided that
they are recruited during training (Andersen and
Henricksson 1977, Nygaard and Nielsen 1978). If
studies of acclimatization to high altitude involve
increased levels of exercise, it is important to take
account of this effect. Table 10.1 compares some of
the tissue changes caused by training with those
resulting from exposure to high altitude.

10.5

MUSCLE FIBER SIZE

As indicated above, one way to increase capillary

density and thus reduce diffusion distance within
skeletal muscle is to reduce the size of the muscle
fibers. There is now good evidence that this occurs
during high altitude acclimatization (Boutellier et
al 1983, Cerretelli et al. 1984, MacDougall et al.
1991). This topic is discussed further in Chapter
14.
The mechanism of muscle atrophy at high altitude
is not well understood. It has been suggested that one
contributing factor is lack of muscular activity.
Certainly lowlanders who go to very high altitudes
easily become fatigued and often spend much of
their time at a reduced level of physical activity.

Indeed Tilman (1952, p. 79) once remarked that a

hazard of Himalayan expeditions was bedsores!
However, reduced physical activity is unlikely to
be the whole story as evidenced by the experience
obtained on the 1960-1 Himalayan Scientific and
Mountaineering Expedition. During several months
at 5800 m, the level of physical activity was well
maintained with opportunities for daily skiing and
yet the expedition members suffered a relentless and
progressive loss of weight which averaged 0.5-1.5 kg
per week (Pugh 1964b). Moreover, estimates of
energy intake were made and these were apparently
more than adequate for the level of activity. It is true
that appetite is reduced, and it may be that gastrointestinal absorption is impaired at high altitude
(Chapter 14), However, it seems possible that there is
some change in protein metabolism which results in
extensive breakdown of muscle protein.

10.6

VOLUME OF MITOCHONDRIA

The muscle mitochondria are the primary sites of

oxygen utilization by the body and thus constitute
the final link of the oxygen cascade. In general, mitochondrial volume density (volume of mitochondria
per unit volume of tissue) in skeletal muscle is related
to maximal oxygen uptake and, for example, is
greater in highly aerobic animals such as the horse

126 Peripheral tissues

compared with less active animals such as the cow

(Hoppeler etal. 1987). It is also known that physical
training increases mitochondrial volume density
(Holloszy and Coyle 1984).
We might therefore expect that at high altitude
where maximal oxygen uptake is reduced (Chapter
11) mitochondrial density would decrease. However,
Ou and Tenney (1970) showed that the number of
mitochondria in samples of myocardium was
40 per cent greater in cattle born and raised at
4250 m compared with cattle at sea level (Figure
10.5). The size of individual mitochondria was found
to be the same and it was argued that the increase in
mitochondrial number was advantageous because it
reduced the diffusion distance of the intracellular
oxygen. However, these interesting results may not
apply to all species. Another investigation of the
mitochondrial density of the myocardium of rabbits
and guinea-pigs from Cerro de Pasco (4330 m) in
Peru compared with those at sea level showed no
increase in density (Kearney 1973).
Recent work indicates that the mitochondrial volume in human skeletal muscle decreases with exposure to very high altitude. In a study on muscle
biopsies of climbers returning from two Swiss
Himalayan expeditions, mitochondrial volume
decreased by 20 per cent. This was associated with a

decrease of 10 per cent in muscle mass. The net result

was a decrease in absolute mitochondrial volume of
nearly 30 per cent (Hoppeler et al 1990). There was
no significant increase in mitochondrial volume density in biopsies of vastus lateralis in subjects of
Operation Everest II (MacDougall etal. 1991).
It may be that these discordant results can be
explained by the differences between exposure to
moderate and very high altitude. The increase in
mitochondrial number found by Ou and Tenney
(1970) was at an altitude of 4500 m, whereas the
decrease in mitochondrial volume reported by
Hoppeler et al. (1990) was in climbers who had been
to altitudes over 6000 m. This is relevant to the discussion of high altitude acclimatization which occurs
at moderate altitudes, and high altitude deterioration
which occurs at extremely high altitudes, as discussed
in Chapter 4.
There is an interesting difference between the
mitochondrial density following exposure to high
altitude on the one hand, and endurance training at
sea level on the other, in their differential effects on
subsarcolemmal and interfibrillar mitochondria.
There is a greater loss of subsarcolemmal mitochondria at altitude, while subsarcolemmal mitochondria
show a greater increase with training at sea level
(Desplanches et al. 1993, Cerretelli and Hoppeler
1996).

10.7

Figure 10.5 Increase in number of mitochondria in myocardium

of cattle bom and raised at 4250 m (ALT) compared with another
group born and raised at sea level (SL). The left-hand columns
show the number of mitochondria (x 1011) per gram of wet tissue;
the right hand columns show the number (x 10n) per gram of
tissue protein. (Data from Ou and Tenney 1970.)

MYOGLOBIN CONCENTRATION

As stated above, early studies by Hurtado and his colleagues (1937) showed increased concentrations of
myoglobin in several muscles of dogs born and raised
in Morococha (4550 m) in Peru. The controls were
dogs in Lima at sea level. Increased myoglobin concentrations were found in the diaphragm, adductor
muscles of the leg, pectoral muscles of the chest and
the myocardium (Figure 10.6).
Reynafarje (1962) measured myoglobin concentrations in the sartorius muscle of healthy humans
native to Cerro de Pasco (4400 m) and in other
Peruvians native to sea level. Higher concentrations
of myoglobin were found in the high altitude natives
(7.03 mg g~: tissue) than in the sea level controls
(6.07 mg g"1)- The result was interpreted as a true
high altitude effect because it was accompanied by an
increased nitrogen content of the muscle, whereas

Intracellular enzymes 127

Figure 10.6 Myoglobin concentration

(mg lOOg-1 of muscle) from seven sea level dogs
compared with seven born and raised at
4540 m. (From Hurtado et al. 1937.)

the lean body mass and body water content were the
same as at sea level. This point was important
because in another study (Anthony et al. 1959), a
reported increase in myoglobin content of skeletal
muscle in rats could possibly have been caused by a
decrease in body weight as a result of dehydration.
Other studies which have shown an increase in myoglobin as a result of acclimatization to hypoxia
include those of hamster heart muscle (Clark et al.
1952), rat heart and diaphragm (Vaughan and Pace
1956) and various guinea-pig tissues (Tappan and
Reynafarje 1957).
As discussed above, the chief value of myoglobin
may be that it facilitates oxygen diffusion through
muscle cells. However, it may also serve to buffer
regional differences of P02 (Figure 10.3) and act as an
oxygen store for short periods of very severe oxygen
deprivation. It has been shown that increased levels
of exercise raise the myoglobin content of muscles in
experimental animals (Lawrie 1953, Pattengale and
Holloszy 1967). Animals that exhibit large oxygen
uptakes in conditions of reduced oxygen availability,
such as seals, typically have very large amounts of
myoglobin (Castellini and Somero 1981). However,
a study comparing trained and untrained human
subjects (Jansson et al. 1982) and another study of
short-term training in humans (Svedenhag et al.
1983) both failed to show any effect of training on
muscle myoglobin concentration.
10.8

INTRACELLULAR ENZYMES

Enzymes are essential to all aspects of the metabolic

pathways involved in energy production. Figure 10.7

summarizes the three main stages in energy metabolism:

the conversion of glucose units (from either glucose or glycogen, known as glycolysis), amino
acids and fatty acids to acetyl CoA
the citric acid or Krebs cycle
the electron transport chain.
Because oxygen is not required for the glycolytic
breakdown of glucose or glycogen, glycolysis represents an important though temporary source of
energy under conditions of oxygen shortage or
absence. By contrast, neither the Krebs cycle nor the
electron transport chain can produce energy in the
absence of oxygen.
There is evidence that chronic hypoxia caused by
moderate or high altitude increases the concentration or activities of certain important enzymes
involved in oxidative metabolism, but hypoxia does
not appear to affect enzymes in the glycolytic pathway. However, it must be stressed that endurance
exercise training also causes profound changes in the
oxidative enzyme systems and it is difficult to maintain a given level of physical activity during exposure
to chronic hypoxia. Similarly, it is also difficult to
match sea level residents with residents at altitude
with respect to physical activity.
Perhaps the first study of the enzymatic activity of
human muscle at high altitude was that by
Reynafarje (1962). The measurements were made on
biopsies taken from the sartorius muscles of natives
of Cerro de Pasco (4400 m) and these were compared
with biopsies from residents of Lima at sea level.
Reynafarje measured the activities of enzymes of
glycolysis (lactate dehydrogenase), Krebs cycle

128 Peripheral tissues

Figure 10.7 Major energy-yielding pathways in muscle. The principal controlling enzymes are indicated. Altitude or hypoxic exposure and
exercise training do not affect glycolytic capacity appreciably but cause substantial increases in oxidative capacity as demonstrated by
augmented mitochondria! volume in some species and activity of major enzymes of the citric acid cycle and the electron transport chain.

Intracellular enzymes 129

(isocitrate dehydrogenase), and the electron transport chain (NADH and NADPH-cytochrome
c-reductase and NAD[P] + transhydrogenase). In this
study Reynafarje found that the activities of
NADH-oxidase, NADPH-cytochrome c-reductase
and NAD[P] + transhydrogenase were significantly
increased in the altitude residents.
Harris etal. (1970) reported on the levels of succinate dehydrogenase (Krebs cycle) and lactate dehydrogenase (glycolysis) activity in myocardial
homogenates from guinea-pigs, rabbits and dogs
indigenous to high altitude (4380 m) and compared
the measurements with those made on the same
species at sea level. They found a consistent increase
in the activity of succinate dehydrogenase in the high
altitude animals but no significant difference in lactate dehydrogenase. Ou and Tenney (1970) also
found increased levels of succinate dehydrogenase
and several enzymes of the electron transport chain
including cytochrome oxidase, NADH-oxidase and
NADH-cytochrome c-reductase in high altitude
cattle.
In contrast to the effects of moderately high altitude (4000-5000 m), it appears that extreme altitude
(above 6000 m) may cause a reduction in the activity
of certain enzymes. The effect of exposure to extreme
altitude on muscle enzyme systems has been studied
by taking muscle biopsies from climbers before and
after the Swiss expeditions to Lhotse Shar in 1981
(Cerretelli 1987) and Mount Everest in 1986
(Howald et al. 1990) and also from experimental
subjects before and after prolonged decompression
during Operation Everest II (Green et al. 1989). All
of these studies reported decreased activities of
oxidative enzymes. Results on three subjects from
the Lhotse Shar expedition suggest that extreme
altitude reduces the activity of both Krebs cycle
(succinate dehydrogenase) and glycolytic (phosphofructokinase and lactate dehydrogenase) enzymes
(Cerretelli 1987). In a more comprehensive study of
seven climbers from the Swiss 1986 expedition,
reduced activity of enzymes of the Krebs cycle (citrate synthase, malate dehydrogenase) and electron

transport chain (cytochrome oxidase) were reported

(Howald et al. 1990). In contrast to the Lhotse Shar
study, this latter study found increases in enzyme
activities of glycolysis. In Operation Everest II, significant reductions were found in succinate dehydrogenase (21 per cent), citrate synthase (37 per cent)
and hexokinase (53 per cent) at extreme altitudes
(Green etal 1989).
Interestingly, the enhanced capacity for oxidative
metabolism found in the face of an unchanged glycolytic potential after high altitude (below 5000 m)
exposure is qualitatively similar to the changes found
in skeletal muscle after endurance exercise training
(Holloszy and Coyle 1984). This observation supports the notion that tissue hypoxia may be responsible for the changes in mitochondrial density and
oxidative enzyme capacity under both conditions.
However, as pointed out earlier, there are differences
between the two stresses, for example in the intracellular distribution of mitochondria.
It has been argued that the primary importance of
an augmented oxidative capacity of skeletal muscle
lies not in the ability to achieve a higher maximum
oxygen uptake but, rather, to sustain a given submaximal oxygen uptake with less intracellular metabolic disturbance (i.e. change of ADP and inorganic
phosphate (P;), both potent stimulators of glycolysis)
(Gollnick and Saltin 1982, Holloszy and Coyle 1984,
Dudley et al. 1987). Thus, for strenuous exercise
where fatigue is associated with depletion of muscle
glycogen stores, an augmented muscle oxidative
capacity enables a given oxygen uptake to be sustained at lower intracellular ADP and Pt concentrations. Consequently, muscle glycogen stores would
be conserved and fat oxidation would contribute
proportionally more to the energetic output of the
muscle, resulting in an enhanced endurance capacity
(Holloszy and Coyle 1984, Dudley et al 1987). In
conclusion, these changes in tissue enzymes (with the
exception of those at extreme altitudes) are consistent with the assumption that the muscles are
improving their ability for oxidative metabolism in
the face of oxygen deprivation or deficiency.

11
Exercise
11.1
11.2
11.3
11.4
11.5

Introduction
Historical
Ventilation
Diffusion
Ventilation/perfusion relationships

130
131
133
135
135

SUMMARY
Exercise at high altitude makes enormous demands
on the oxygen transfer system of the body because of
the increased oxygen uptake in the face of the reduced
inspired P0r Consequently, reduced exercise tolerance is one of the most obvious features of exposure
to high altitude. Maximal exercise is accompanied by
extremely high ventilations (measured at body
temperature and pressure); these can approach
200 L min"1 at extreme altitudes, which is close to the
maximum voluntary ventilation. Diffusion limitation
of oxygen transfer across the blood-gas barrier is an
important limiting factor. As a result, arterial P02 levels typically fall greatly as the work rate is increased.
Some additional ventilation/perfusion inequality also
often develops, possibly because of subclinical pulmonary edema. Maximal cardiac output is reduced at
high altitude, although, in acclimatized subjects, the
relationship between cardiac output and work rate is
the same as at sea level. Maximal oxygen consumption in acclimatized subjects falls from about
4-5 L min"1 at sea level to just over 1 L min"1 at the
Everest summit. Part of the reduction in V02 max can
be ascribed to diffusion limitation within the exercising muscle. The oxygen consumption for a given work
rate is independent of altitude. Although aerobic
performance is greatly impaired at high altitude, there
is no change in maximal anaerobic peak power (for

11.6
11.7
11.8
11.9
11.10

Cardiovascular responses
Arterial blood gases
Peripheral tissues
Maximal oxygen uptake at high altitude
Anaerobic performance at high altitude

136
136
137
139
141

example as measured by a standing jump) unless muscle mass is reduced.

11.1

INTRODUCTION

The hypoxia of high altitude puts stress on the

oxygen transfer system of the body even at rest. If the
oxygen requirements are further increased by
exercise, the problems of oxygen delivery to the
mitochondria of the working muscles are correspondingly exaggerated. Indeed, one of the most
obvious consequences of going to high altitude is a
reduced exercise tolerance.
In this chapter we examine the physiology of
oxygen transfer from the air to the mitochondria in
the face of the reduced inspired P02. The steps in the
oxygen cascade include getting the oxygen to the
alveoli via pulmonary ventilation, diffusion of
oxygen across the blood-gas barrier, uptake by the
pulmonary capillary blood, removal from the lung
by the cardiac output, transport to the tissues via the
arterial blood, diffusion of oxygen to the mitochondria and utilization of oxygen by the cellular
biochemical reactions. The present chapter
synthesizes information, some of which occurs in
other chapters. The subject of limitation of oxygen
uptake under the conditions of extreme altitude is
dealt with in Chapter 12. The literature on exercise at

Historical 131

altitude is very extensive and the present chapter is

necessarily selective. Many monographs and reviews
have been published including Margaria (1967),
Cerretelli and Whipp (1980), Sutton et al. (1983
1987), Cerretelli (1992) and Wagner (1996).

11.2

HISTORICAL

A reduced exercise tolerance at high altitude has been

recognized since humans began to climb high
mountains. For example, extreme fatigue was often
reported in the early climbs of the European Alps
and in fact this led to one of the popular theories of
mountain sickness. The argument ran that the
normal barometric pressure was necessary to
maintain the proper articulation of the head of the
femur in the acetabulum of the pelvis, and that at
high altitude, when the reduced barometric pressure
did not assist this as it should, the muscles became
fatigued as a result (Bert 1878, pp. 343-6).
Some of the earliest measurements of exercise at
high altitude were made by Zuntz, Durig and their
colleagues in the first few years of the twentieth
century (Zuntz et al. 1906, Durig 1911). For example,
Zuntz showed that there was a decline in oxygen consumption but increase in ventilation at high altitude
when trekkers walked at the speed that they normally
adopted in an Alpine setting. Douglas, Haldane and
their colleagues (1913) studied muscular exercise
during walking uphill on Pikes Peak during the
Anglo-American Expedition of 1911. They made the
important observation that a given amount of work
required the same amount of oxygen at 4300 m
altitude as at sea level.
Colorful descriptions of the great difficulties of
exercise at very high altitudes were common in the
early Everest expeditions. Indeed, the accounts of
the 1921 reconnaissance expedition (Howard-Bury
1922), and the expeditions of 1922 (Bruce 1923) and
1924 (Norton 1925) make graphic reading even
today. Typical is E. F. Norton's account of his climb
to nearly 8600 m without supplementary oxygen in
1924 (Norton 1925, pp. 90-119). Rewrote
... our pace was wretched. My ambition was to do
twenty consecutive paces uphill without a pause to
rest and pant, elbow on bent knee, yet I never
remember achieving it - thirteen was nearer the
mark. (Norton 1925, p. 111)

Norton was accompanied to just below that

altitude by the surgeon T.H. Somervell who
subsequently wrote 'for every step forward and
upward, 7 to 10 complete respirations were required'
(Somervell 1936).
Of course, these were observations by lowlanders
who were at extreme altitudes after relatively short
periods of time for acclimatization. It is interesting to
compare the observations of Barcroft who led an
expedition at about the same time (winter of 1921-2)
to Cerro de Pasco at an altitude of 4330 m in the
Peruvian Andes (Barcroft et al. 1923). Naturally this
was at a considerably lower altitude than near the
summit of Mount Everest. Nevertheless, the lowlanders were amazed at the capacity of the high
altitude residents for physical work, and they were
astonished at the popularity of energetic sports such
as soccer. The contrast between poorly acclimatized
lowlanders and native high altitude dwellers, who
had been at the same altitude for perhaps
generations, was very clear.
Valuable findings on exercise at high altitude were
made during the 1935 International High Altitude
Expedition to Chile (Keys 1936). The expedition
members studied their own maximal working
capacity and showed how this fell as the altitude
increased despite acclimatization. Christensen
(1937) made measurements up to an altitude of
5340 m using a bicycle ergometer and confirmed the
findings of Douglas etal. (1913) that the efficiency of
muscle exercise was independent of altitude, that is
that the oxygen consumption for a given work level
was the same. In addition he showed that although
exercise ventilation measured at BTPS (body
temperature, ambient pressure, saturated with water
vapor) was greatly increased at high altitudes, ventilation expressed at STPD (standard temperature and
pressure, dry gas) was essentially independent of
altitude over a wide range of altitudes and work rates.
An interesting observation was made by Edwards
who documented a curious paradox about lactate
levels in the blood on exercise. Generally, exhaustive
exercise is accompanied by relatively high blood
lactate levels, especially in unfit subjects, as the
muscles outstrip their capacity for aerobic work and
resort to anaerobic glycolysis. It would be natural to
expect this to occur to an extreme extent at high
altitude, as it does in acute hypoxia, but Edwards
found the opposite. Exhaustive work at very high
altitude was associated with very low levels of blood

132 Exercise

lactate (Edwards 1936). Dill and colleagues (1931)

had previously seen the same phenomenon in a
similar series of measurements.
The expedition members were also surprised by
the tolerance of the miners for energetic physical
activity at the Aucanquilcha mine, which they
believed was at an altitude of 5800 m. We now know
that the mine is actually higher, the altitude being
5950 m. The exercise level of the miners is indeed
astonishing as they break large pieces of sulfur ore
(caliche) with sledgehammers (Mclntyre 1987). The
miners are predominantly Bolivians who were born
at moderately high altitudes and since most of them
live at Amincha (altitude 4200 m) they have a
considerable degree of high altitude acclimatization.
In preparation for the British Mount Everest
expedition of 1953, Pugh measured oxygen uptakes
on climbers in the field near Cho Oyu in the Nepal
Himalayas in 1952. These data were then used to
determine the amount of oxygen to be carried by the
1953 expedition during which Pugh made further
measurements of exercise physiology (Pugh 1958). He
subsequently greatly extended this programme in the
ambitious Himalayan Scientific and Mountaineering
Expedition (Silver Hut) of 1960-1 in which several
physiologists spent the winter in a prefabricated hut at
an altitude of 5800 m (Pugh 1962a). Further measurements of maximal oxygen consumption were carried
out in the spring when the expedition moved to
Mount Makalu (8481 m) and a bicycle ergometer was
erected on the Makalu Col (altitude 7440 m) (Figure
1.8). Those measurements of maximal work remain
the highest ever made (Pugh et al. 1964). The data
assembled by Pugh and his co-workers (Figure 11.1)
were of great interest because they predicted that, near
the summit of Mount Everest, the maximal oxygen
uptake would be very close to the basal oxygen
requirements, and therefore it seemed problematic
whether humans could ever reach the summit without
supplementary oxygen (West and Wagner 1980).
Additional measurements of maximal oxygen
consumption were made by Cerretelli during an
Italian expedition to Mount Everest in 1973
(Cerretelli 1976a). All the data were obtained at Base
Camp (altitude 5350 m) but they included measurements on climbers who had been above 8000 m. One
of the many interesting observations was the failure
of the maximal oxygen uptake of acclimatized
subjects at 5350 m to return to the sea level value
when pure oxygen was breathed. The explanation of

Figure 11.1 V02 max against barometric pressure in acclimatized

subjects (9, xj as reported by Pugh et al. (1964). Data from
normal climbing rates are also shown (O).

this finding, also made by Pugh and others, is still

controversial.
The issue of whether the partial pressure of oxygen
at the summit of Mount Everest was sufficient for
humans to reach it without supplementary oxygen
was finally answered in 1978 by Reinhold Messner
and Peter Habeler. However, their accounts make it
clear that neither had much in reserve (Habeler 1979,
Messner 1979). The intriguing question of how the
body is just able to transport sufficient oxygen to the
exercising muscles under these conditions of profound hypoxia is considered in detail in Chapter 12.
During the 1981 American Medical Research
Expedition to Everest (AMREE), extensive measurements of maximal oxygen uptake were made in the
main laboratory camp, altitude 6300 m. However,
data were also obtained for exercise at higher
altitudes by giving the well acclimatized subjects
inspired mixtures containing low concentrations of
oxygen. For example, when the inspired P0z was only
42.5 mm Hg, corresponding to that on the summit of
Mount Everest, the measured maximal oxygen
consumption was just over 1 L min"1 (West et al.
1983c). Although this is very low, being equivalent to
that of someone walking slowly on the level, it is

Ventilation 133

apparently just sufficient to explain how a climber

can reach the summit without supplementary
oxygen (Chapter 12).
A further extensive series of exercise measurements was made during Operation Everest II in the
autumn of 1985 (Houston et al. 1987). The eight
subjects spent 40 days in a large low pressure
chamber being gradually decompressed to the
barometric pressure existing at the summit of Mount
Everest, and a series of measurements of maximal
exercise was made using a bicycle ergometer. The
measured oxygen consumptions agreed well with
those found in the field by the 1981 expedition
(Sutton et al. 1988), but Operation Everest II had the
great additional advantage that many invasive
measurements could be made which were impracticable in the field. These included extensive measurements of pulmonary vascular pressures, muscle
volume and muscle biopsies (Sutton et al. 1987).

113

VENTILATION

Exercise at high altitude is accompanied by very high

levels of ventilation. Indeed, this was one of the most
obvious features of climbing at extreme altitudes in
the early Everest expeditions, as evidenced by the
quotations from Norton and Somervell in the
preceding section.
Ventilation is normally expressed at body
temperature, ambient pressure and with the gas
saturated with water vapor (BTPS). This is because
the volumes of gas moved then correspond to the
volume excursions of the chest and lungs.
Ventilation can also be expressed at standard
temperature and pressure for dry gas (STPD). These
volumes are very much smaller at high altitude and
bear no obvious relationship to the actual chest
movements. However, the oxygen consumption and
carbon dioxide output are traditionally expressed in
these units so that the values are independent of
altitude.
For a given work level, the ventilation expressed as
BTPS increases at high altitude. Typical results are
shown in Figure 11.2b, which shows data obtained
during the 1960-1 Silver Hut expedition (Pugh et al.
1964). Figure 11.2c shows ventilations expressed as
STPD. Here the values also tend to be somewhat
higher than those measured at sea level, especially at

Figure 11.2 Relationship between ventilation, both BTPS and

STPD, and oxygen uptake at various altitudes. Heart rate is also
shown. (From Pugh et al. 1964.)

work levels approaching the maximum for the

altitude, but the differences are clearly much less
than for ventilation expressed as BTPS.
Ventilation (BTPS) can reach extremely high
levels, as evidenced by data obtained during the 1981
AMREE expedition at an altitude of 6300 m (PB
351 mmHg). In eight subjects who exercised at a
work rate of 1200 kg mirr1, the mean ventilation
(BTPS) was 207 L min"1 with a mean respiratory
frequency of 62 breaths min"1. These values were for
a mean oxygen consumption of 2.31 L min'1. These
levels of ventilation far exceed anything ever seen at
sea level and are approaching the maximal voluntary
ventilation (MW), that is the maximal amount of
air that can be moved per minute by breathing in and
out as rapidly and deeply as possible, usually measured over 15 s.
It is interesting that these extremely high levels of
ventilation are not seen at the highest altitudes. For
example, when two subjects on the 1981 expedition

134 Exercise

were given a 14 per cent oxygen mixture to breathe at

an altitude of 6300 m (inspired P02 42.5 mm Hg), the
maximal exercise ventilation was only 162 L min~'.
This inspired P02 corresponded to that at the Everest
summit. A reasonable explanation for the lower
exercise ventilation is that the work rate was very
much lower, being only 450 kgm min"1 as opposed to
1200 kgm min-1 at the altitude of 6300 m while
breathing air. Another possibility is that the
respiratory muscles were limited by the severe hypoxemia. Figure 11.3 shows maximal exercise ventilation
plotted against inspired P0l (dashed line) and the fact
that there is a maximal value is clearly seen, although
there are only four points on the curve. A similar pattern was found during the 1960-1 expedition. For
example, the maximal exercise ventilation at 5800 m
had a mean value of 173 L min"1. At the higher altitude of 6400 m this had fallen to 161 L min-1, while at
the highest altitude of 7440 m, the value was only
122 L min"1. Corresponding to the fall in maximal
exercise ventilation, the work rate decreased from
1200 kgm min-1 at 5800 m, to 900 kgm min-1 at
6400 m, to 600 kgm min-1 at 7400 m.
These extremely high exercise ventilations are
facilitated by the reduced work of breathing as a
result of the lowered density of the air at high
altitude. The reduced density also results in an

increased MW (or maximum breathing capacity) as

altitude is increased (Cotes 1954). For example,
Cotes showed that the MW (BTPS) increased from
158 L min"1 at sea level to 197 L min"1 at a simulated
altitude of 5180 m in a low pressure chamber. In a
further study, a mean value of 203 L min"1 was
observed at a simulated altitude of 8250 m (Cotes
1954). The increase in MW was compatible with the
hypothesis that the work of maximum breathing
remains constant at high altitude. The reduction in
the work of breathing at high altitude caused by the
change in gas density was also analyzed by Petit et al.
(1963).
Oxygen breathing reduces exercise ventilation for
a given work rate at high altitude. However, as Figure
11.4 shows, the ventilations do not return to the sea
level values but are intermediate between the high
altitude and sea level values for ambient air.
The pattern of breathing during exercise at high
altitude is characterized by very high frequencies and
relatively small tidal volumes. Somervell's observation, referred to in section 11.2, of 7-10 complete
respirations per step is evidence for that. The highest
measurements of respiratory frequency and tidal

Figure 11.3 Maximal ventilation (BTPS), maximal respiratory

frequency, and maximal heart rate plotted against inspired P02 on
a log scale. This scale was chosen only because otherwise the high
altitude points fall very close together. Note that both maximal
ventilation and heart rate fall at extreme altitudes because work

Figure 11.4 Effect of breathing oxygen at sea level pressure on

levels become so low. However, respiratory frequency continues to

ventilation and heart rate in acclimatized subjects at 5800 m. The

increase. (From West et al. 1983a.)

points are mean values from two subjects. (From Pugh et al. 1964.)

Ventilation/perfusion relationships 135

volume yet made were those on Pizzo during the

1981 Everest expedition (West et al 1983c). Pizzo
climbed for about 7 min at an altitude of 8300 m (PB
271 mm Hg) while measuring his ventilation with a
turbine flow meter, and the output was registered on
a slow-running tape recorder. During the middle
4 min of this period, his mean respiratory frequency
was 86 2.8 (SD) breaths min"1, mean tidal volume
was 1.26 L, and mean ventilation was 107 L min"1 at
BTPS. Thus his breathing was shallow and extremely
rapid. Reference has already been made to the measurements of maximal exercise at an inspired P02 of
42.5 mmHg corresponding to that on the Everest
summit which was obtained by making the subjects
inspire 14 per cent oxygen at an altitude of 6300 m.
For two subjects, the mean respiratory frequency was
80 breaths min"1.
This pattern of breathing is consistent with the
very powerful hypoxic drive via the peripheral
chemoreceptors. As pointed out in Chapter 5, it is
remarkable that the hypoxic drive is so strong under
these conditions because the arterial PC02 is less than
10 mm Hg and the arterial pH is over 7.7. A very low
Pcc,2 and high pH normally inhibit ventilation.

11.4

DIFFUSION

As discussed in Chapter 6, there is strong evidence

that diffusion limitation of oxygen transfer in the
lung occurs during exercise at high altitude. This is
the primary reason for the progressive fall in arterial
P02 and arterial oxygen saturation which has been
consistently observed. Analysis of the situation at
extreme altitude indicates that the diffusing capacity
of the blood-gas barrier is one of the chief limiting
factors for maximal exercise (Chapter 12).
There is no evidence that the diffusing capacity of
the blood-gas barrier increases during acclimatization to high altitude in normal subjects. Measurements from the 1960-1 Silver Hut Expedition
showed that the diffusing capacity of the blood-gas
barrier for a given level of exercise was the same as at
sea level (West 1962a). Overall pulmonary diffusing
capacity for carbon monoxide increased by
19 per cent at an altitude of 5800 m, but this could be
attributed to the more rapid rate of combination of
carbon monoxide with oxygen because of the low
prevailing P02. The volume of blood in the

pulmonary capillaries as determined by measuring

the diffusing capacity at two values of alveolar P02
showed no change or possibly a slight fall. This may
have been due to hypoxic pulmonary vasoconstriction.
These results also imply that, in acclimatized
subjects, the transit time for red cells in the
pulmonary capillaries at a given work level is
approximately the same as at sea level. The transit
time of the pulmonary capillary blood is given by the
pulmonary capillary blood volume divided by the
cardiac output (Roughton 1945). As discussed in
Chapter 7, there is good evidence that, in acclimatized lowlanders at high altitude, the cardiac output
for a given work level is the same as at sea level (Pugh
1964c, Reeves et al. 1987). Thus, since both the
pulmonary capillary blood volume and the cardiac
output are essentially unchanged, this indicates that
the transit time through the pulmonary capillaries
will also be the same as at sea level.

11.5
VENTILATION/PERFUSION
RELATIONSHIPS
Until recently it was believed that the only change in
ventilation/perfusion relationships at high altitude
was a more uniform topographical distribution of
blood flow. This is caused by the increased
pulmonary arterial pressure as a result of hypoxic
pulmonary vasoconstriction (Chapter 7). For
example, measurements with radioactive xenon have
shown that the topographical differences of blood
flow between apex and base of the upright lung are
reduced at an altitude of 3100 m (Dawson 1972). As
discussed in Chapter 12, measurements by Wagner
and his co-workers show a broadening of the
distribution of ventilation/perfusion ratios during
severe exercise at high altitude, the cause of which is
still uncertain. The change in the distribution takes
the form of a shoulder on the left of the blood flow
distribution (plotted against ventilation/perfusion
ratio), that is, an increase in blood flow to poorly
ventilated lung units.
These changes have now been seen in normal
subjects who are exercising while acutely exposed to
hypoxia in a low pressure chamber (Gale et al. 1985),
exercising normal subjects who are inhaling low
oxygen mixtures (Hammond etal. 1986) and normal

136 Exercise

subjects during a 40-day exposure to low pressure in

a chamber during Operation Everest II (Wagner et al.
1988a). Evidence from this last study suggests that
the ventilation/perfusion abnormalities are most
likely to be seen in poorly acclimatized subjects after
a rapid ascent. In general, the abnormalities were
most marked at the most severe levels of hypoxia,
and at the heaviest exercise levels.
A reasonable hypothesis is that these changes are
caused in some way by subclinical pulmonary edema
which results in inequality of ventilation. As
discussed in Chapter 19, high altitude pulmonary
edema (RAPE) is a well known complication of
going to high altitude. The likely mechanism is
uneven hypoxic pulmonary vasoconstriction, which
allows some capillaries to be exposed to high
pressure with subsequent damage to their walls
(West and Mathieu-Costello 1992a). The increase in
pulmonary artery pressure is exaggerated during
heavy exercise (Groves etal. 1987).

11.6

CARDIOVASCULAR RESPONSES

The cardiovascular effects of altitude are discussed in

Chapter 7. In nonacclimatized and poorly acclimatized lowlanders who go to high altitude, cardiac
output at rest and during exercise for a given work
level is increased compared with sea level values. The
same is true of heart rate.
In acclimatized lowlanders, cardiac output for a
given work level returns to its sea level value, as
shown by Pugh (1964c) during the 1960-1 Silver Hut
Expedition, and more recently during Operation
Everest II (Reeves et al. 1987). However, heart rate
for a given level of exercise remains higher at altitude
and therefore stroke volume is less. Measurements of
contractile function of the heart during Operation
Everest II in exercising subjects at all altitudes
showed remarkable preservation despite the very
severe hypoxemia (Reeves et al. 1987).
Pulmonary artery pressures are increased during
exercise at altitude compared with sea level values at
the same work level. The elevated pressures are seen
in both unacclimatized (Kronenberg et al. 1971) and
acclimatized (Groves et al. 1987) lowlanders, and in
native highlanders (Penaloza et al. 1963, Lockhart et
al. 1976). The basic cause of the pulmonary hypertension is presumably hypoxic pulmonary vaso-

constriction. However, it is of considerable interest

that in the subjects of Operation Everest II the
pulmonary vascular pressures did not return to
normal when 100 per cent oxygen was breathed,
even though the subjects had been at high altitude
for only 2-3 weeks (Groves et al. 1987). This indicates some structural changes (remodeling) in the
pulmonary arteries in addition to hypoxic vasoconstriction.

11J

ARTERIAL BLOOD GASES

At high altitude, the resting pattern of a low arterial

P02 and Pcc,2 is also seen during exercise. Arterial P02
typically falls further on exercise because of diffusion
limitation. In addition, at high work levels, the
arterial Pcc,2 often falls below the resting value,
indicating that alveolar ventilation increases more
than carbon dioxide production. The falling PC02 is
associated with an increased respiratory exchange
ratio, which may rise to values over 1.2 at the highest
work loads at very high altitudes (West et al. 1983c).
This represents an unsteady state since the respiratory quotient of the metabolizing tissues cannot
exceed 1.0. At sea level, such an increase in respiratory exchange ratio is often associated with lactate
production from exercising muscles as a result of
anaerobic glycolysis. However, at very high altitude,
blood lactate levels remain surprisingly low even
following exhausting exercise (Edwards 1936,
Cerretelli 1980, West 1986c).
Arterial pH is near normal in well acclimatized
subjects up to altitudes of about 5400 m, though
Winslow obtained evidence that there is often a small
degree of uncompensated respiratory alkalosis, even
in native highlanders (Winslow et al. 1981, Winslow
and Monge 1987). At higher altitudes the arterial pH
at rest tends to increase and it exceeds 7.7 on the
Everest summit (West et al. 1983b). The respiratory
alkalosis is exaggerated on exercise because the
arterial Pcc,2 tends to fall and levels of blood lactate
are low.
As stated in section 11.2, extensive observations
that blood lactate is low in acclimatized subjects at
high altitude, even during maximal work, were first
made by Edwards (1936) during the 1935
International High Altitude Expedition to Chile,
although Dill et al. (1931) had obtained some data

Peripheral tissues 137

Figure 11.5 Venous blood lactate after exercise

as reported by Edwards from the 1935
International High Altitude Expedition to Chile.
The lines are drawn through the sea level values.
In general, lactate levels at high altitude lie on the
same line, the only obvious exceptions being
measurements made at the lowest altitude of
2.81 km. The small figures above these points
indicate the number of days spent at that altitude
and in most instances this was insufficient for
acclimatization. (From Edwards 1936.)

prior to that. Figure 11.5 is redrawn from Edward's

paper and shows that the levels of blood lactate
during exercise at high altitude (up to 5340 m) were
essentially the same as at sea level. This means that
the blood lactate levels for a given work level were
apparently independent of tissue P02. The only clear
exceptions to this were the points shown by the open
circles which were obtained at the lowest altitude of
2810 m. The small numbers over these points
indicate the number of days that the subject had
spent at this lowest altitude when the measurement
was made, and it is clear that in most instances these
data were obtained before the subject had had time
to become fully acclimatized. Since maximal work
capacity declines markedly with increasing altitude,
the data of Figure 11.5 imply that maximal blood
lactate falls in acclimatized subjects as altitude
increases.
These results have been extended by Cerretelli
(1976a,b, 1980) with additional measurements made
at an altitude of 6300 m on the 1981 AMREE
expedition (West et al. 1983c). Figure 12.5 summarizes the data on resting and maximal blood
lactate (West 1986c) and suggests the surprising
conclusion that, after maximal exercise at altitudes
exceeding 7500 m, there will be no increase in lactate
in the blood at all despite the extreme oxygen deprivation. Possible reasons for this are discussed in
more detail in Chapter 12.

11.8

PERIPHERAL TISSUES

The changes that occur in peripheral tissues at high

altitude were discussed in Chapter 10. Animal studies
indicate an increase in capillary density in some
tissues as a result of chronic hypoxia. However, data
available from human muscle biopsies indicate that
the number of capillaries remains constant in
acclimatized lowlanders, but the average distance
over which oxygen diffuses is reduced because the
muscle fibers become smaller. There are changes in
intracellular enzymes, and some studies show an
increase in muscle myoglobin which may enhance
oxygen diffusion. All these factors will play an
important role in oxygen delivery and utilization
during exercise.
Recently there has been considerable interest in
the possible role of oxygen diffusion from capillaries
to mitochondria as a factor-limiting exercise at high
altitude. Traditionally, many physiologists have
argued that the power of working muscles at high
altitude is determined by the amount of oxygen
reaching them via the arterial blood. Oxygen
delivery, defined as the arterial oxygen concentration
multiplied by the blood flow to the muscle, has often
been regarded as the critical variable.
Wagner and his co-workers have analyzed the
relationship between oxygen uptake and the P02 of

138 Exercise

Figure 11.6 (a) How V02 max is determined, assuming that

oxygen diffusion from the peripheral capillary to the mitochondria
is the limiting factor. The two lines show the oxygen uptake
available from the Pick principle on the one hand, and Pick's law
of diffusion on the other. The V02max is given by the intersection of
the two lines. See text for details. (From Wagner) (b) As (a) except
an additional line has been added to represent the Pick equation
at high altitude. This reduces the V02max as shown. See text for
details. (From Wagner.)

muscle capillary blood on the assumption that the

uptake is limited by oxygen diffusion from the
capillaries to the mitochondria (Hogan etal. 1988a).
Figure 11.6a shows the relation of oxygen uptake to
the P02 of muscle venous blood, taken as an index of
muscle capillary P02. The line sloping from top left to
bottom right shows the amount of oxygen being
delivered to the muscle by the capillaries (Pick
principle). The line from bottom left to top right
shows the pressure gradient available to cause oxygen
diffusion from the red cells to the mitochondria
(Pick's law) assuming that the mitochondrial P02 is

nearly zero. The slope of this line is the lumped

'diffusing capacity for oxygen' of the tissues. The
point where the two diagonal lines cross represents
the Vo2max- Regions to the left of this indicate
situations where ample oxygen is available in the
blood but the diffusing head of pressure is
inadequate. Regions to the right indicate a more than
adequate diffusing head of pressure but inadequate
amounts of oxygen in the blood.
Figure 11.6b shows the same diagram with
another line added indicating the presumed situation
at high altitude. Because the oxygen concentration of
the arterial blood is low, the line representing the
Pick principle is displaced downwards and to the left.
The Vo2 max is therefore lower. The diagram assumes
that the 'diffusing capacity for oxygen' of the tissue is
the same at sea level and at altitude. It could be
argued that this is not the case if the diffusing
distance is reduced by the appearance of more
capillaries, or the size of muscle fibers is reduced.
However, experimental evidence indicates that these
factors are relatively unimportant and that the diffusing capacity is essentially determined by the number of open capillaries (Hepple etal. 2000). This is in
line with the fact that most of the fall in P02 is
believed to be at the capillary wall (see Chapter 10),
and that the myoglobin or other mechanisms of
enhanced intracellular transport make the diffusion
distance unimportant.
Several pieces of evidence now support this
concept. For example, a retrospective analysis of data
from Operation Everest II showed that the points
relating the P02 of mixed venous blood to oxygen
uptake tend to lie on a straight line passing through
the origin. On the assumption that the P02 of mixed
venous blood reflects the P02 of the blood in the
capillaries of the exercising muscles, this relationship
supports the notion. Indeed, it was this observation
that prompted the hypothesis.
More direct evidence comes from a prospective
study in which normal subjects exercised at high
work loads breathing hypoxic mixtures, and samples
of femoral venous blood were taken via an indwelling
catheter (Roca etal. 1989). Again a plot of the P02 of
femoral venous blood against oxygen uptake for
different inspired oxygen concentrations showed the
points lying close to a straight line passing near to the
origin. A similar plot was found when the calculated
mean capillary P02 was substituted for femoral
venous P02.

Maximal oxygen uptake at high altitude 139

Additional studies have been carried out on an

isolated dog gastrocnemius preparation where the
muscle was supplied with hypoxic blood and stimulated maximally. Again a good relationship was
found between the P02 of the effluent blood and the
maximal oxygen uptake at different levels of hypoxia
(Hogan et al. 1988a). This preparation allowed a test
of two competing hypotheses, that referred to above,
and an alternative hypothesis that V"02max is determined by the amount of oxygen delivered to the
muscle via the blood. The test was made by supplying
the isolated muscle with the same amounts of oxygen
(arterial oxygen concentration x blood flow) but
using different blood flows (and therefore oxygen
concentrations). The results showed that V02miOL was
more closely related to the P02 of muscle venous
blood than to the oxygen delivered via the arterial
blood, and therefore the results support the
hypothesis of diffusion limitation (Hogan et al.
1988b).
The diffusion limitation hypothesis has also been
tested in more recent studies. In one, the oxygen
affinity of hemoglobin was increased by feeding dogs
sodium cyanate and it was shown that for the same
convective oxygen delivery (cardiac output x arterial
oxygen concentration) the maximal oxygen concentration of dog muscle was reduced compared with
animals in which the oxygen affinity was normal
(Hogan et al. 1991). The converse experiment was
also carried out by reducing the oxygen affinity of
hemoglobin using the allosteric modifier methylpropionic acid. In this case, the dog muscle showed
an increased maximal oxygen consumption at a
constant blood oxygen delivery compared with an
animal with a normal oxygen affinity of hemoglobin
(Richardson et al. 1998). There therefore are considerable experimental data supporting the analysis
shown in Figure 11.6.

11.9
MAXIMAL OXYGEN UPTAKE AT
HIGH ALTITUDE

Figure 11.7 (a) V02max as a percentage of the sea level

value plotted against barometric pressure and altitude. (O, Aj,
acute hypoxia; (9), chronic hypoxia; (x), high altitude natives. See
original text for complete explanation of symbols. (From Cerretelli

Many investigators have documented the fall in

maximal oxygen uptake at high altitude since the
early studies of Zuntz et al. (1906), and the results of
Pugh and his co-workers are shown in Figure 11.1.
Figure 11.7a shows data from a number of studies
collated by Cerretelli (1980). Note that, even at the

1980.) (b) Maximal oxygen uptake against inspired P02 as

measured on the 1981 American Medical Research Expedition to
Everest. The lowest point was obtained by giving well acclimatized
subjects at an altitude of 6300 m an inspired gas mixture
containing 14 per cent oxygen. The inspired ?02 was 42.5 mm Hg,
which is equivalent to that on the Everest summit. Compare Figure
11.1. (Modified from West el al. 1983a.)

140 Exercise

very modest altitude of 2500 m, there is already an

average decrease of Vo2max of 5-10 per cent as
compared to sea level. Cerretelli pointed out that
these data do not show any consistent differences
between subjects exposed to acute hypoxia and those
who have had the advantage of acclimatization to
high altitude. This conclusion goes against the
experience of many climbers who feel that they can
work harder at high altitude after acclimatization,
and the conclusion cannot presumably be true at the
most extreme altitudes where acute exposure to the
prevailing barometric pressure (for example on
the summit of Mount Everest) results in loss of
consciousness within a few minutes in most unacclimatized individuals. It is of interest that elite
high altitude climbers have only moderately high
levels of maximal oxygen consumption at sea level
(Oeketal. 1986).
These data on maximal oxygen uptake were
extended by the 1981 AMREE studies, where
measurements were made at an altitude of 6300 m on
subjects breathing ambient air, but also breathing 16
and 14 per cent oxygen (West et al. 1983c). The last
gave an inspired P02 of 42.5 mm Hg, equivalent to
that on the Everest summit. The results are shown in
Figure 11.7b, where it can be seen that in these
subjects who were well acclimatized to very high
altitude, the Vo2max fell to 15.3 mL min-1 kg-1 O2,
which was equivalent to 1.07 L min"1. Thus at the
highest point on Earth, the maximal oxygen uptake is
reduced to between 20 per cent and 25 per cent of the
sea level value. As pointed out in Chapter 12, this
oxygen uptake is equivalent to that seen when a
subject walks slowly on the level but nevertheless is
apparently sufficient to explain how Messner and
Habeler were able to reach the Everest summit
without supplementary oxygen in 1978. Indeed,
Messner's statement that the last 100 m took more
than an hour to climb fits with this measured oxygen
uptake (Messner 1979).
Measurements of V02msx at various altitudes were
also made during Operation Everest II and the data
are almost superimposable on those shown in Figure
11.7b at the highest altitudes (Sutton et al 1987).
This is interesting because the subjects of Operation
Everest II were probably not as well acclimatized to
the extreme altitudes as the members of the 1981
expedition, as judged from their alveolar gas
composition and other measurements (West 1993b).
The values for Vo2max at any given altitude as

determined by the 1981 Everest expedition (Figure

11.7b) are higher than those earlier reported by Pugh
et al. (1964) based on measurements made during
the Silver Hut Expedition and previous measurements on Mount Everest. This can be explained by
the higher level of fitness of subjects on the 1981
expedition. For example, several of the AMREE
members were competitive marathon runners.
Several studies since the early measurements of
Douglas et al. (1913) have shown that the relationship between oxygen uptake and work rate (or
power) is independent of altitude. Figure 11.8a
shows a comparison of data from the 1960-1
Himalayan Scientific and Mountaineering Expedition, and Figure 11.8b from the 1981 Everest
expedition. The message of the two plots is the same,
but note the much higher work rates at sea level
recorded prior to the 1981 expedition which provide
further evidence of the high level of athletic ability of
these subjects.
As indicated earlier, breathing pure oxygen at high
altitude does not return the V02max to the sea level
value, as shown by Cerretelli (1976a) and others. The
reason is unclear; the opposite might be expected
since the subjects acclimatized to high altitude have
higher blood hemoglobin levels. However, against
this are the results of a more recent study showing
that when erythrocytes were infused into lowlanders
after 1 or 9 days at an altitude of 4300 m, there was no
improvement in the decreased V^max (Young et al.
1996). It has been suggested that the reduced Vo2max
is caused by the loss of muscle mass at high altitude,
and that if V02 max were related to lean body mass, the
reduction would not be found. As discussed in
Chapter 10, the diameter of muscle fibers decreases
during acclimatization. Another possibility is that
the increased red cell concentration causes uneven
blood flow and sludging in peripheral capillaries and
this interferes with oxygen unloading.
Does a period of acclimatization at high altitude
improve V02mOL at sea level? Again the answer is not
clear. Cerretelli (1976a) measured Vo2max m a grouP
of subjects at sea level shortly before they were exposed
to an altitude of 5350 m for 10-12 weeks, and again
at sea level about 4 weeks after return from altitude.
Although there was an approximately 11 per cent
increase in hemoglobin concentration, this was not
accompanied by a statistically significant rise in
Vo2max. On the other hand, more recent studies involving the reinjection of a subject's own red cells in order

Anaerobic performance at high altitude 141

to raise the hematocrit have shown a small but significant increase in Vo2max at sea level (Spriet etal. 1986).
This result would suggest that a period at medium altitude (certainly lower than 5350m) may improve exercise tolerance at sea level. Perhaps the reduction of
muscle fiber size at very high altitudes is the explanation for the failure to see an increase in V02 max after
acclimatization at very high altitude. As noted above,
red cell infusions into lowlanders exposed to an altitude of 4300 m for 1 or 9 days did not improve the
Vo2max at that altitude (Young et al. 1996).
It should be pointed out that the Vo2max determined
at any particular altitude is something of an artificial
measurement because climbers, for example, do not
ordinarily exercise at that intensity. Pugh (1958)
showed that climbers typically select an oxygen uptake
of one-half to three-quarters of their maximum for
normal climbing at altitudes up to 6000 m. Actual
values of oxygen uptake measured by Pugh during
normal climbing are included in Figure 11.1.

11.10
ANAEROBIC PERFORMANCE AT
HIGH ALTITUDE

Figure 11.8 (a) Oxygen uptake plotted against work rate at

various altitudes during the Silver Hut Expedition showing that the
relationship remains essentially the same as at sea level. (From
Pugh et al. 1964.) (b) Similar plot as in (a) but showing the much
higher work rates at sea level obtained during the 1981AMREE.
(From Westeta\. 1983a.)

Reference has already been made to the paradoxically

low levels of blood lactate following exhaustive
exercise at extreme altitude (section 11.7, Figure
11.5). This phenomenon may be related to the
reduced plasma bicarbonate concentration which
interferes with buffering of hydrogen ion, as discussed
in Chapter 12. Cerretelli (1992) has shown that the
rate of increase of V02 when exercise is suddenly
begun was slower in subjects after return from the
1981 Swiss Lhotse Expedition compared with before
departure. This finding may be related to changes in
anaerobic performance. However, it was also shown
that maximal anaerobic (alactic) 'peak' power as measured by a standing jump was not affected by exposure of up to 3 weeks at 5200 m. Thereafter it tended
to fall along with the reduction of muscle mass.

12
Limiting factors at extreme altitude
12.1 Introduction
12.2 Historical
12.3 Physiology of extreme altitude

142
143
145

SUMMARY
The fact that a well acclimatized human can just
reach the highest point on Earth without breathing
supplementary oxygen is an extraordinary coincidence. Several experimental and theoretical studies
in the early part of the twentieth century predicted
that this would not be possible, and therefore it was
of great interest when Messner and Habeler realized
the feat in 1978. A critical factor is the higher barometric pressure in the great mountain ranges at latitudes near the equator than that predicted by the
standard atmosphere. Another critical factor is the
extreme hyperventilation that the successful climber
generates, thus forcing his alveolar PC02 below
10 mm Hg and consequently defending his alveolar
P02 at viable levels. Also important is the extreme respiratory alkalosis that increases the oxygen affinity of
hemoglobin and thus assists in the loading of oxygen
by the pulmonary capillary. Even so, the maximal
oxygen consumption on the summit of Everest is
only just above 1 L mirr1, and the arterial P0z is less
than 30 mm Hg during physical work. The analysis
of the physiological conditions near the Everest summit explains why tragedies occur when unexpected
circumstances arise, such as deterioration of the
weather. The fact that normal humans can survive

12.4 What limits exercise performance at

extreme altitude?

152

the extreme derangement of blood gases which is

necessary for these climbs to extreme altitudes is a
graphic reminder of the resilience of the human
organism.

12.1

INTRODUCTION

It is a remarkable coincidence that when humans

are well acclimatized to high altitude, they can just
reach the highest point on Earth without breathing
supplementary oxygen. This feat was only realized
in 1978 and many physiologists and physicians
interested in high altitude had previously predicted
that it would not be possible (West 1998). It was
truly the end of an era when Messner and Habeler
stood on the summit of Mount Everest on 8 May
1978.
This chapter examines the profound physiological
changes that are necessary for humans to survive and
do small amounts of work at extreme altitudes like
the summit of Mount Everest. It includes an analysis
of the factors that limit performance at these great
altitudes and shows that such ascents are possible
only if both the physiological make-up of the climber
and physical factors such as barometric pressure are
right.

Historical 143

12.2

HISTORICAL

12.2.1 Sixteenth to nineteenth

centuries
It has been known for many centuries that very high
altitude has a deleterious effect on the human body
and that the amount of work that a person can do
becomes more and more limited as the altitude
increases. One of the first descriptions of the disabling effects of high altitude was given by the Jesuit
missionary Joseph de Acosta who accompanied the
early Spanish conquistadores to Peru in the sixteenth
century. He described how, as he traveled over a high
mountain, he 'was suddenly surprised with so mortall and strange a pang, that I was ready to fall from
the top to the ground.' His dramatic description was
first published in 1590 (Acosta 1590).
In the eighteenth century, climbers in the
European Alps reported a variety of disagreeable sensations which now seem to us greatly exaggerated.
For example, the physicist De Saussure, who was the
third person to reach the summit of Mont Blanc,
reported during the climb:
When I began this ascent, I was quite out of breath
from the rarity of the air ...

The kind of fatigue

which results from the rarity of the air is absolutely

unconquerable; when it is at its height, the most
terrible danger would not make you take a single
step further.

When he was near the summit he complained of

extreme exhaustion:
This need of rest was absolutely unconquerable; if I
tried to overcome it, my legs refused to move, I felt
the beginning of a faint, and was seized by dizziness. ..

On the summit itself he reported:

made of higher mountains, including those in the

Andes, and there were abundant accounts of the disabling effects of extreme altitude. In 1879, Whymper
made the first ascent of Chimborazo and described
how, at an altitude of 16 664 ft (5079 m), he was incapacitated by the thin air:
...

in about an hour I found myself lying on my

back, along with both the Carrels [his

guides],

placed hors de combat, and incapable of making

the least exertion ... We were unable to satisfy our
desire for air, except by breathing with open
mouths ...

Besides having our normal rate of

breathing largely accelerated, we found it impossible to sustain life without every now and then giving spasmodic gulps, just like fishes when taken out
of water (Whymper 1892).

However, Whymper and his two guides gradually

recovered their strength and in fact his lively account
shows that he was aware of the beneficial effects of
high altitude acclimatization.
In the latter part of the nineteenth century, there
was considerable interest in the highest altitude that
could be tolerated by climbers. Thomas W. Hinchliff,
President of the (British) Alpine Club (1875-7),
wrote an account of his travels around the world and
described his feelings as he looked at the view from
Santiago in Chile.
Lover of mountains as I am, and familiar with such
summits as those of Mont Blanc, Monte Rosa, and
other Alpine heights, I could not repress a strange
feeling as I looked at Tupungato and Aconcagua,
and reflected that endless successions of men must
in all probability be forever debarred from their
lofty crests ...

Those who, like Major Godwin

Austen, have had all the advantages of experience

and acclimatization to aid them in attacks upon the
higher Himalayas, agree that 21 500 ft [6553 m] is
near the limit at which man ceases to be capable of
the slightest further exertion (Hinchliff 1876).

When I had to get to work to set out the instruments

and observe them, I was constantly forced to interrupt my work and devote myself to breathing (de
Saussure, 1786-7).

These dramatic complaints at an altitude of only

4807 m or less reflect a combination of an almost
complete lack of acclimatization and the fear of the
unknown.
In the nineteenth century numerous ascents were

12.2.2

Twentieth century

In 1909, the Duke of Abruzzi attempted an ascent of

K2 in the Karakoram Mountains, and although his
party was unsuccessful in reaching the summit, they
reached the remarkable altitude of 7500 m without
supplementary oxygen. According to the Duke's

144 Limiting factors at extreme altitude

biographer, one of the reasons given for this expedition was 'to see how high man can go' (de Fillippi
1912), and certainly the climb had a dramatic effect
on both the mountaineering and the medical communities interested in high altitude tolerance. In
contrast to the florid accounts of paralyzing fatigue
and breathlessness given by De Saussure, Whymper
and others at much lower altitudes, the Duke made
light of the physiological problems associated with
this great altitude. However, as we saw earlier
(Chapter 6), his feat prompted heated arguments
among physiologists about whether the lungs
actively secreted oxygen at this previously unheard of
altitude.
Ten years later, a milestone in the history of the
physiology of extreme altitude was provided by the
British physiologist, Alexander M. Kellas, whose contributions have been almost completely overlooked.
Kellas was lecturer in chemistry at the Middlesex
Hospital Medical School in London during the first
two decades of the century, but, despite this fulltime
faculty position, managed to make eight expeditions
to the Himalayas, and probably spent more time
above 20000 ft (6100 m) than anyone else. In 1919
he wrote an extensive paper entitled 'A consideration
of the possibility of ascending Mount Everest', which
unfortunately was only published in French in a very
obscure place (Kellas 1921). In this he analyzed the
physiology of a climber near the Everest summit,
including a discussion of the summit altitude, barometric pressure, alveolar P0z, arterial oxygen saturation, maximal oxygen consumption and maximal
ascent rate. On the basis of his study he concluded
that
Mount Everest could be ascended by a man of excellent physical and mental constitution in first-rate
training, without adventitious aids [supplementary
oxygen] if the physical difficulties of the mountain
are not too great.

The importance of this study was not so much that

he reached the correct conclusion. He had so few
data that many of his calculations were incorrect.
However, Kellas asked all the right questions and he
can claim the distinction of being the first physiologist to seriously analyze the limiting factors at the
highest point on Earth. It was not until almost
60 years later that all his predictions were fulfilled.
Kellas was a member of the first official reconnaissance expedition to Everest in 1921, but tragically he

died during the approach march just as the expedition had its first view of the mountain they came to
climb. Three years later, E. F. Norton, who was a
member of the third Everest expedition, reached a
height of about 8589 m (28150 ft) on the north side
of Everest without supplementary oxygen. He was
accompanied to just below that altitude by Dr T. H.
Somervell, who collected alveolar gas samples at an
altitude of 7010 m, though unfortunately these were
stored in rubber bladders through which the carbon
dioxide rapidly diffused (Somervell 1925). Somervell
also referred to the extreme breathlessness at that
altitude, stating that 'for every step forward and
upward, 7 to 10 complete respirations were
required'.
The summit of Everest was finally attained in 1953
by Hillary and Tensing (Hunt 1953). Naturally, this
was a landmark event in the physiology of extreme
altitude, but the fact that the two climbers used supplementary oxygen still did not answer the question
of whether it was possible to reach the summit
breathing air. Hillary did remove his oxygen mask on
the summit for about 10 min and at the end of the
time reported
I realized that I was becoming rather clumsy-fingered and slow-moving, so I quickly replaced my
oxygen set and experienced once more the stimulating effect of even a few litres of oxygen.

Nevertheless, the fact that he could survive for a few

minutes without additional oxygen came as a surprise to some physicians who had predicted that he
would lose consciousness.
However, there was a precedent for surviving for
this period on the summit in the experiment
Operation Everest I, carried out by Houston and
Riley in 1945. As briefly described in Chapter 1, four
volunteers spent 34 days in a low pressure chamber
and two were able to tolerate 20 min without supplementary oxygen on the 'summit'. In fact, the equivalent altitude was even higher because the standard
atmosphere pressure was inadvertently used (section
12.3.2).
Additional information on whether there was
enough oxygen in the air to allow a climber to reach
the Everest summit while breathing air was obtained
by Pugh and his colleagues during the 1960-1
Himalayan Scientific and Mountaineering (Silver
Hut) Expedition (Pugh etal. 1964). Measurements of
maximal oxygen consumption were made using a

Physiology of extreme altitude 145

bicycle ergometer on a group of physiologists who

wintered at an altitude of 5800 m and who were
therefore extremely well acclimatized to this altitude.
Figure 12.1 (lower curve) shows the results of
measurements made up to an altitude of 7440 m.
Note that extrapolation of the line to a barometric
pressure of 250 mm Hg on the Everest summit suggested that almost all the oxygen available would be
required for the basal oxygen uptake. (For details of
the extrapolation procedure, refer to West and
Wagner 1980.) Thus these results strongly suggested
that a climber who could reach the Everest summit
without supplementary oxygen would be very near
the limit of human tolerance.
This ultimate climbing achievement occurred
when Reinhold Messner and Peter Habeler reached
the summit of Everest without supplementary oxygen in May 1978. Messner's account (Messner 1979)
makes it clear that he had very little in reserve:
After every few steps, we huddle over our ice axes,
mouths agape, struggling for sufficient breath . . .
As we get higher it becomes necessary to lie down
to recover our breath ... Breathing becomes such a
strenuous business that we scarcely have strength
to go on.

And when he eventually reaches the summit:

In my state of spiritual abstraction, I no longer
belong to myself and to my eyesight. I am nothing
more than a single, narrow gasping lung, floating
over the mists and the summits.

The long period of 25 years between the first

ascent of Everest in 1953 and this first 'oxygenless'
ascent also suggests that we are near the limit of
human tolerance. Again, as indicated earlier, Norton
and Somervell ascended to within 300 m of the
Everest summit as early as 1924, but it was not until
1978 that climbers reached the top without supplementary oxygen. Thus the last 300 m took 54 years!
Since that historic climb, Messner has further confirmed his outstanding tolerance to the extreme
hypoxia of great altitudes. In 1980, he became the
first man to ascend Everest alone without supplementary oxygen (Messner 1981), and in 1986 he
became the first man to climb all 14 of the 8000 m
peaks without supplementary oxygen. These accomplishments assure him a place not only in the history
of mountaineering but also in the history of the
physiology of extreme altitude.

123
PHYSIOLOGY OF EXTREME
ALTITUDE

123.1

Figure 12.1 Maximal oxygen uptake against inspired P0/ The

lower line shows data from Pugh et al. (1964) suggesting that all
the oxygen available at the Everest summit would be required for
basal oxygen uptake. However, as the upper line shows, the 1981
AMREE measured an oxygen uptake of just over 1 L min~1 for an
inspired P02 of 43 mm Hg. (From West et al. 1983a.)

Introduction

This section is devoted to human performance at

altitudes over 8000 m. There has been a renewed
interest in this topic since Messner and Habeler
climbed Everest without supplementary oxygen in
1978 but, as indicated above, the issue of whether
humans would be able to tolerate the highest altitude
on Earth was raised early in this century, notably by
Kellasinl919.
The following analysis is based primarily on data
from three studies. The first was the 1960-1 Silver
Hut Expedition during which data were obtained on
maximal oxygen consumptions as high as 7440 m (PB
300 mm Hg) and alveolar gas samples were taken as
high as 7830 m (PB 288 mmHg). These measurements were extended to the Everest summit by the
1981 American Medical Research Expedition to
Everest (AMREE), where measurements on the summit included barometric pressure, alveolar gas sam-

146 Limiting factors at extreme altitude

pies and electrocardiograms, with additional

measurements made between the summit and the
highest camp situated at 8050 m (PB 284 mmHg).
The third study was Operation Everest II in 1985
when eight volunteers were gradually decompressed
to a barometric pressure of 240 mm Hg over a period
of 40 days in a low pressure chamber. Although the
rate of simulated ascent was too fast for optimal
acclimatization, many valuable data were obtained,
particularly in the areas of cardiopulmonary and
muscle physiology.

123.2

Barometric pressure

Barometric pressure is a critical variable in physiological performance at extreme altitude because it

determines the inspired P02. This is the first link in
the chain of the oxygen cascade from the atmosphere
to the mitochondria. As pointed out in Chapter 2,
there has been considerable confusion in the past
about the relationships between barometric pressure
and altitude on high mountains such as the
Himalayan chain. The resulting errors are particularly important at extreme altitude because it can be
shown that maximal oxygen consumption is exquisitely sensitive to barometric pressure. It is remarkable that Paul Bert gave essentially the correct value
of barometric pressure for the Everest summit in
Appendix I of his classic book La Pression
Barometrique (Bert 1878). His figure of 248 mmHg
was based on an extrapolation of measurements
made by Jourdanet at various locations including the
Andes (Jourdanet 1875).
However, when the standard atmosphere was
introduced and used extensively by aviation physiologists in the 1930s and 1940s, it was erroneously
applied to Mount Everest, giving a value of
236 mm Hg, which was much too low. Nevertheless,
this figure was used by several high altitude physiologists. For example, during Operation Everest I when
four naval recruits were gradually decompressed to
what was thought to be the simulated altitude of
Mount Everest, they were exposed to a pressure of
236 mm Hg and their alveolar P02 fell to as low as
21 mm Hg (Riley and Houston 1950-1)! As the next
section shows, this is about 14 mm Hg less than that
of a well acclimatized climber on the summit of
Mount Everest.
As described in Chapter 2, Dr Christopher Pizzo

measured a barometric pressure of 253 mm Hg on

the Everest summit on 24 October 1981. This was
about 2 mm Hg higher than that expected from the
mean barometric pressure for that month based on
extensive weather balloon data (Figure 2.4). The discrepancy can be accounted for by normal variation
and the high pressure system which made the
weather ideal for climbing. The reading of
253 mm Hg was within 1 mm Hg of the pressure predicted for an altitude of 8848 m from radiosonde balloons released in New Delhi, India, on the same day
(West etal. 1983a).
As section 12.4 shows, exercise performance at
these extreme altitudes is exquisitely sensitive to
barometric pressure. This is chiefly because the lung
is working very low on the oxygen dissociation curve
where the slope is steep. As a consequence, a fall of
barometric pressure of as little as 3 mm Hg (less than
twice the daily standard deviation) will apparently
cause a reduction of maximal oxygen uptake of over
5 per cent. This means that even the daily variations
of barometric pressure caused by weather can affect
physical performance.
Seasonal variations of barometric pressure can be
expected to have a marked effect on maximal oxygen
uptake. As Figure 2.2 shows, mean barometric pressure falls from nearly 255 mmHg in the summer
months to only 243 mmHg in mid-winter. This
decrease is predicted to reduce maximal oxygen
uptake by some 25 per cent. It is noteworthy that
Mount Everest has only once been climbed during
winter without supplementary oxygen (in December
1987), despite several attempts, and although the
very cold temperatures and high winds are naturally
a factor, the reduced barometric pressure must certainly contribute (section 2.2.8).
As pointed out in Chapter 2, the location of
Mount Everest at 28N latitude is fortunate because
the barometric pressure at its summit is considerably
higher than would be the case if it were at a higher
latitude. As an example, if Mount McKinley were
8848 m high, its barometric pressure for May and
October (preferred climbing months for Everest)
would be only 223 mm Hg. It would apparently be
impossible to reach the summit without supplementary oxygen under these conditions.
A similar argument would apply if the barometric
pressure on the Everest summit were only
236 mm Hg, as predicted from the standard atmosphere model. The reduction of pressure by

Physiology of extreme altitude 147

17 mmHg below that measured by Pizzo would

reduce the maximal oxygen consumption by over
30 per cent, according to the analysis presented in the
present chapter. It seems very probable that climbing
Everest without supplementary oxygen under these
conditions would be impossible. Thus the higher
pressure that Everest enjoys because of its near equatorial latitude makes it just possible for humans to
reach the highest point on Earth.

1233

Alveolar gas composition

On ascent to high altitude, the alveolar P02 falls

because of the reduction in the inspired P02. At the
same time, alveolar PC02 falls because of increasing
hyperventilation. As described in Chapter 5, Rahn
and Otis (1949) clarified the differences between
unacclimatized and fully acclimatized subjects at
high altitude by plotting their alveolar gas P02 and
PCo2 values on an oxygen-carbon dioxide diagram
(Figure 5.4).
Figure 12.2 shows alveolar Pcc,2 plotted against
barometric pressure at extreme altitude. The closed
circles show data reported by Greene (1934), Warren
(1939), Pugh (1957) and Gill etal (1962). The triangles show data obtained on the AMREE (West et al.
1983b). It can be seen that alveolar PC02 declines
approximately linearly as barometric pressure falls
and that the pressure on the summit of Mount
Everest is about 7-8 mm Hg. The measurements

made on the summit itself had high respiratory

exchange ratio (R) values, for reasons which are not
clear. However, the data obtained at the slightly
lower altitude of 8400 m (PB 267 mm Hg) had a mean
R value of 0.82 with a PC02 of 8.0 mm Hg, which
means we can be confident of the very low values at
this great altitude.
Figure 12.3 shows the line drawn by Rahn and
Otis (1949) for fully acclimatized subjects (lower
line on Figure 5.4) together with additional data
obtained at barometric pressures below 350 mm Hg
(Table 12.1). Note that the AMREE data (triangles)
fit well with the extrapolation of the line. This
method of plotting the data shows that, as well
acclimatized humans go to higher and higher altitudes, the P02 falls because of the decreasing
inspired P0l, and the PC02 falls because of the
increasing hyperventilation. However, above an
altitude of about 7000 m (PB 325 mm Hg) the alveolar P02 becomes essentially constant at a value of
about 35 mmHg. More recent measurements of
alveolar P02 up to an altitude of 8000 m by Peacock
and Jones (1997) are in good agreement with these
data. This means that successful climbers are able to
defend their alveolar P02 by the process of extreme
hyperventilation. In other words, they insulate the
P02 of their alveolar gas from the falling value in
the atmosphere around them. This appears to be
the most important feature of acclimatization at
extreme altitude.

Figure 12.2 Alveolar PC(,2 against barometric pressure at extreme

altitudes. Triangles show the means of measurements on the

Figure 12.3 Oxygen-carbon dioxide diagram showing alveolar

AMREE. Circles are results from previous Investigators at

gas values collated by Rahn and Otis (1949) (circles) together with

barometric pressures below 350 mm Hg (Table 12.1). (From West et

values obtained at extreme altitudes by the AMREE (triangles)

a I. 1983b.)

(From West etal. 1983b.)

148 Limiting factors at extreme altitude

Table 12.1 Alveolar P02 and PC02 in acclimatized subjects at barometric pressures
below 350 mm Hg

Greene (1934)

337

40.7

305

43.0

17.7

0.87

9.2

0.79
0.60

Warren (1939)

337a

37.0

15.6

Pugh(1957)

347

39.3

21.0

0.87

337
308

35.5
34.1

21.3
16.9

0.87
0.77

344

38.1

20.7

0.82

300
288

33.7
32.8

15.8
14.3

0.78
0.77

284

36.1

11.0

0.78

267
253

36.7
37.6

8.0
7.5

0.82
1.49

Gil I etal. (1962)

West et al. (1983b)

All pressure values are given in mm Hg.

a
Barometric pressure estimated from curve of Zuntzeto/. (1906).

Not everyone can generate the enormous increase

in ventilation required for the very low PC02 values
shown in Figures 12.2 and 12.3. This explains why
climbers with a large hypoxic ventilatory response
usually tolerate extreme altitude better than those
with a more modest response (Schoene et al. 1984).
Indeed, experience on the AMREE showed that
individuals who had an unusually low hypoxic ventilatory response were not able to remain at the higher
camps (West 1985a).
The pattern of alveolar gas values shown in
Figure 12.3 is only obtained if sufficient time is
allowed for full respiratory acclimatization. Figure
12.4 compares the results found in unacclimatized
and fully acclimatized subjects at high altitude
(Figures 5.4, 12.3) with alveolar gas data reported
from two low pressure chamber experiments in
which the simulated rate of ascent was much faster.
It can be seen that in Operation Everest I (Riley and
Houston 1950-1) the subjects reached the simulated summit after only 31 days and at the extreme
altitudes the data fell close to the region predicted
by the line for unacclimatized humans. In
Operation Everest II (Malconian et al. 1993) the
ascent was a little slower, with the first simulated
summit excursion occurring after 36 days.
However, the alveolar gas values at extreme altitudes still deviated considerably from those found
in fully acclimatized subjects. Little information is
available about the time required for full respiratory
acclimatization at extreme altitudes, say over

8000 m, but Figure 12.4 suggests that 36 days is

inadequate whereas 77 days is apparently sufficient.
However, it may be that other factors such as the
level of physical activity are also important.

Figure 12.4 Oxygen-carbon dioxide diagram showing the two

lines described by Rahn and Otis (1949) for unacclimatized and
acclimatized subjects at high altitude (compare Figure 5.4). In
addition, data from Operation Everest I (Of. I) and Operation
Everest II (OEII) are included. Note that the OEI subjects were
poorly acclimatized at extreme altitudes whereas the OE II had
intermediate values. (From West 1998.)

Physiology of extreme altitude 149

123.4

Acid-base status

Relatively little is known about acid-base changes at

extreme altitude, despite the importance of this
topic. Some data are available from two well acclimatized subjects of the AMREE, based on blood samples
removed during the morning after they had reached
the summit. Venous blood samples taken at the highest camp (8050 m; PB 267 mm Hg) showed a mean
base excess of-7.2 mmol L"1. This was a considerably
higher base excess than expected (in other words the
base deficit was less than predicted) and the result
was an extremely high arterial pH of over 7.7 calculated for the Everest summit (West et al. 1983b). This
calculation assumes that there was no change in base
excess in the previous 24 h and that a climber resting
on the summit had a negligible blood lactate concentration (see below). In addition, the measured
alveolar PC02 of 7.5 mm Hg is assumed to apply to the
arterial blood.
A remarkable feature of these base excess values is
that they were essentially unchanged from those
measured in 14 subjects living for several weeks at
Camp 2 (6300 m, PB 351 mmHg) where the mean
value was -8.7 1.7 mmol Ir1 (Winslow etal. 1984).
This suggests that base excess was changing
extremely slowly above an altitude of 6300 m. The
reason for this is not known but may be related to the
chronic volume depletion which was observed in
climbers living at 6300 m. At this altitude the serum
osmolality was 302 4 mmol kg~', which was significantly higher (p < 0.01) than in the same subjects at
sea level, where the value was 290 1 mmol kg"1
(Blume et al 1984). It is known that the kidney gives
a higher priority to correcting dehydration than
acid-base disturbances, and in order to excrete more
bicarbonate to reduce the base excess, it would be
necessary to lose corresponding cations, which
would aggravate the volume depletion. This may be
the basis for the slow renal bicarbonate excretion.
These acid-base changes maybe part of the explanation of why climbers can spend only a relatively
short time at extreme altitudes, say above 8000 m. It
was pointed out in Chapter 6 that the marked respiratory alkalosis which increases the oxygen affinity of
the hemoglobin at extreme altitude is beneficial
because it accelerates the loading of oxygen by the
pulmonary capillaries. If a climber remains at
extreme altitude for several days, presumably there is
some renal excretion of bicarbonate (though this

appears to be slow) and the resulting metabolic compensation would move the pH back towards 7.4.
Thus the advantage of a left-shifted dissociation
curve would tend to be lost.
One way to counter this disadvantage during a
climb of Mount Everest would be to put in the high
camps and then return to Base Camp at a lower altitude for several days. This period at medium altitude
would then allow the body to adjust again to this
more moderate oxygen deprivation and enable the
blood pH to stabilize nearer its normal value. The
final summit assault would then be as rapid as possible to take advantage of the nearly uncompensated
respiratory alkalosis. In fact this was the pattern
adopted by Messner and Habeler in their first ascent
of Mount Everest without supplementary oxygen in
1978.
Blood lactate is known to be very low in acclimatized subjects at high altitude even during maximal
work, an observation made by Edwards (1936) during the International High Altitude Expedition to
Chile in 1935. Figure 12.5 shows data on resting and
maximal blood lactate obtained by Cerretelli (1980).
Also shown are measurements made at 6300 m after
maximal exercise at the rate of 900 kg mirr1, that is,
an oxygen uptake of 1.75 L min"1 (West 1986c). The
mean value after exercise at 6300 m was only
3.0 mmol L"1 despite arterial P02 of less than
35 mm Hg and, presumably, extreme tissue hypoxia.

Figure 12.5 Maximal blood lactate (Lab) as a function of altitude.

Most of the data are redrawn from Cerretelli (1980). The filled
circles and triangles show data for acclimatized Caucasians (C); the
open circles and triangles a re for high altitude natives (N). The
data for 6300 m are from the AMREE for acclimatized lowlanders.
(From West 1986.) The points marked Sutton et al. are from
Operation Everest II (Sutton et al. 1988).

150 Limiting factors at extreme altitude

Note that extrapolation of the line relating maximal

blood lactate concentration to altitude suggests that,
after maximal exercise at altitudes exceeding 7500 m,
there will be no increase in lactate in the blood at all
despite the extreme oxygen deprivation. This is
indeed a paradox.
The blood lactate concentrations after maximal
exercise were appreciably higher on Operation
Everest II (Sutton et al. 1988). For example, at an
inspired P02 of 63 mm Hg, the mean lactate concentration following maximal exercise was 4.7 mmol L"1,
that is about 56 per cent higher than on the AMREE
for the same inspired P02. Moreover, the 'summit'
measurements on Operation Everest II gave a blood
lactate concentration of 3.4 mmol L"1, a higher value
than that found at only 6300 m on the AMREE
(Figure 12.5). It is known that the low lactate concentrations following maximal exercise at high altitude come about as a result of high altitude
acclimatization, because acute hypoxia causes very
high lactate levels. Presumably therefore the higher
values seen on Operation Everest II compared with
the AMREE and other field studies can be explained
by the limited degree of acclimatization.
The reasons for the low blood lactate levels following maximal exercise in well acclimatized subjects as
opposed to poorly acclimatized subjects at high altitude are still unclear. One hypothesis is that on acute
exposure to hypoxia, sympathetic stimulation leads
to augmented muscle lactate production and blood
lactate concentration through a beta-adrenergic
mechanism. By contrast, chronic hypoxia causes
beta-adrenergic adaptation and the result is a
reduced lactate response after acclimatization.
However, studies on unacclimatized and acclimatized subjects at 4300 m altitude have not supported
this hypothesis (Brooks et al. 1998). Another hypothesis is that the bicarbonate depletion that occurs as
a result of acclimatization interferes with the buffering of released lactate and hydrogen ions, and the
consequent fall in local pH inhibits the enzyme phosphofructokinase in the glycolytic cycle and thus puts
a brake on glycolysis (Figure 10.7). It is known that
the activity of phosphofructokinase is reduced as the
pH is lowered. Certainly Cerretelli has shown that
the changes in blood hydrogen ion concentration as
a result of increases in blood lactate are higher in
acclimatized than unacclimatized subjects (Cerretelli
1980). However, many other factors affect blood
lactate and the issue is far from settled.

123.5

Cardiac output

Intuitively, it would be reasonable to expect an

increased cardiac output for a given work level at
extreme altitude compared with sea level. It is known
that cardiac output increases as a result of acute
hypoxia (Chapter 7). Furthermore, the oxygen concentration of the arterial blood is extremely low at very
high altitude, and an increase in cardiac output would
be expected to help to compensate for the reduced
oxygen delivery. Paradoxically, however, the relationship between cardiac output and oxygen uptake
in acclimatized subjects at an altitude of 5800 m is
essentially the same as at sea level (Figure 7.2) and this
apparently holds true even at extreme altitudes,
although data are sparse. Reeves etal. (1987) showed
that the sea level relationship was maintained down
to a barometric pressure of 282 mm Hg, and almost
maintained at an inspired P02 equivalent to the summit of Mount Everest, though at that extreme altitude
the cardiac output appeared to be slightly higher
(Figure 7.3). Possibly this apparent paradox can be
explained by the fact that, as the cardiac output is
increased under these very hypoxic conditions, there
is increasing diffusion limitation of oxygen transfer,
both in the lung and in the muscle. In a theoretical
study, Wagner (1996) showed that increasing cardiac
output for the conditions on the Everest summit did
not improve calculated V02 max because of diffusion
limitation (Figure 7.5).

123.6

Pulmonary diffusing capacity

As discussed in Chapter 6, oxygen transfer during

exercise at high altitude is, in part, diffusion limited,
and all calculations suggest that this limitation will be
exaggerated at the extreme altitudes near the summit
of Mount Everest. However, very few data on diffusing capacity at high altitude are available. Available
measurements at an altitude of 5800 m (PB
380 mm Hg) indicate that the diffusing capacity for
carbon monoxide during exercise is essentially
unchanged from the sea level value except for the
expected increase caused by the faster rate of combination of carbon monoxide with hemoglobin under
the prevailing hypoxic conditions (West 1962a).
These data suggest that the diffusing capacity of the
pulmonary membrane itself is unaltered by acclimatization.

Physiology of extreme altitude 151

Measurements of the diffusing capacity for carbon

monoxide at different alveolar P02 values allow calculation of the pulmonary capillary blood volume.
Again, in measurements made at 5800 m, there
appeared to be little change in capillary blood volume, although there was a suggestion that it was
slightly lower, possibly as a result of hypoxic pulmonary vasoconstriction (West 1962a). If we accept
the conclusion that capillary blood volume is
unchanged, and that the cardiac output/oxygen consumption relationship is the same as at sea level (section 12.3.5), this implies that capillary transit time in
the lung is normal since this is given by capillary
blood volume divided by cardiac output (Roughton
1945).
Using these data it is possible to calculate the
changes in P0l along the pulmonary capillary for a
climber at rest on the summit of Mount Everest
(Figure 6.4). This shows that the rate of oxygenation
is extremely slow and that the end-capillary P02 is
much lower than the alveolar value, indicating severe
diffusion limitation of oxygen transfer.

123.7

P02 of venous blood

During maximal exercise at extreme altitude, the

extraction of oxygen by the peripheral tissues
results in very low values of venous P02 in the exercising muscles. This in turn reduces the P0l of
mixed venous blood. In order to analyze the relationships between the many variables and determine what limits exercise performance at extreme
altitude, one possible assumption is that the body
will not tolerate a P02 of mixed venous blood below
a certain value, for example 15 mmHg (West and
Wagner 1980, West 1983). This assumption
received strong support from Operation Everest II,
where direct measurements of the P02 in mixed
venous blood gave very similar values (Sutton et al.
1988). For example, on the 'summit' during 60 W
of exercise, the P02 of mixed venous blood had a
mean value of 14.8 mmHg, and at 120 W, which
was the highest work level, the mean P02 was
13.8 mmHg.

123.8

Heat loss by hyperventilation

Matthews (1932) argued that tolerance to extreme

altitude might be limited by the high rate of heat loss

from the lungs as a result of the extreme

hyperventilation. However, subsequent experience
has not borne this out. Calculations of net heat loss
are complex because the upper respiratory tract acts
as a heat exchanger. During expiration, expired gas
warms the respiratory tract, and this heat is then
available to warm the cold inspired gas. Climbers
who have reached the summit of Mount Everest
without supplementary oxygen have not been
affected by cold beyond the extent expected from the
very low temperatures of the environment. When
Pizzo reached the summit to take his alveolar gas
samples during the course of the AMREE, he became
overheated during the climb and photographs taken
on the summit when he was breathing air show that
he was not even wearing his down jacket, which he
carried with him in his backpack (West 1985a, facing
p. 51).

123.9

Oxygen cost of ventilation

A climber at extreme altitude has considerable

hyperventilation at rest, and even more during moderate exercise. An alveolar PC02 of 7-8 mm Hg was
measured on the Everest summit and, since it is
known that the carbon dioxide production both at
rest and for a given work level is independent of altitude, we can conclude that the alveolar ventilation
on the summit was at least five times the resting
value. Even small amounts of physical activity will
greatly increase this. If we take the normal resting
ventilation to be 7-8 L mnr1, this means that the
resting ventilation on the summit is at least
40 L min-1.
Cibella et al. (1999) studied the oxygen cost of
ventilation in four normal subjects during exercise at
sea level and after a 1-month sojourn at 5050 m.
From simultaneous measurements of esophageal
pressure and lung volume, the mechanical power
(work rate) of breathing was determined. As
expected, maximal exercise ventilation and maximal
power of breathing were higher at high altitude than
at sea level, whereas maximal oxygen uptake was
reduced in all subjects at high altitude. Interestingly,
in three subjects the relationship between mechanical power of breathing and minute ventilation was
the same at sea level and high altitude, whereas in
only one individual was it lower at high altitude for a
given ventilation. It might have been expected that

152 Limiting factors at extreme altitude

the mechanical power of breathing would be reduced

at high altitude in all subjects because of the reduced
density of the air.
Assuming a mechanical efficiency of 5 per cent,
the oxygen cost of breathing at high altitude and sea
level amounted to 26 and 5.5 per cent of t,2max,
respectively. The authors concluded that, at high altitude, the mechanical power of breathing may substantially limit the ability to do external work. They
also calculated what they called the 'critical ventilation', that is the ventilation at which the mechanical
power of breathing was so high that increasing ventilation above this level did not provide additional
oxygen for external work. At the altitude of 5050 m
the maximal exercise ventilation exceeded the critical

ventilation even when the efficiency was assumed to

be as high as 20 per cent (Figure 12.6).

12.4
WHAT LIMITS EXERCISE
PERFORMANCE AT EXTREME ALTITUDE?

12.4*1

Concept of limitation

The oxygen cascade from the atmosphere to the

mitochondria includes the processes of convective
ventilation of oxygen to the alveoli, diffusion of oxygen across the blood-gas barrier, uptake of oxygen
by the hemoglobin in the pulmonary capillaries,

Figure 12.6 Increase in oxygen consumption divided by the increase in ventilation for four subjects at an altitude of 5050 m. The solid line
shows the relationship for total oxygen consumption; the dashed libes show the relationship for the oxygen consumption of the respiratory
muscles, assuming mechanical efficiencies of 5, 10 and 20 per cent. Arrows show the maximal exercise ventilation. The intersection of the
solid and dashed lines shows the critical ventilation above which no increase in external work was possible because the oxygen consumption
of the respiratory muscles was so high. In three of the subjects, the maximum ventilation exceeded the critical ventilation for all assumed
mechanical efficiencies, though in one of the subjects this was only the case for an efficiency of 5 per cent. (From Cibella et

. 1999.)

What limits exercise performance at extreme altitude? 153

convective flow of the blood to the peripheral capillaries, unloading of the oxygen from the hemoglobin,
diffusion to the mitochondria and utilization of oxygen by the electron transport system. How can we
determine to what extent each of these factors is limiting exercise at extreme altitude?
One approach is to use the analogy of a turbine that
is fed by water flowing through a pipe which has a series
of constrictions in it (Figure 12.7). Clearly, all sections
of the pipe limit the flow of water to some extent.
However, a useful description of the extent to which
flow is limited by any particular section of the pipe can
be found by calculating the percentage change in total
flow for a given (say 5 per cent) change in diameter at
that point. In carrying out this calculation, we assume
that all other factors remain unchanged. Clearly, such
an analysis can only be carried out if the whole system
is modeled using a computer.

12.4.2 Limitations to oxygen uptake on

the summit of Mount Everest
The model analysis described above has been carried
out for a hypothetical subject exercising on the summit of Mount Everest (West 1983). Some assumptions and extrapolations are necessary because so few
data have yet been obtained at these great altitudes.
In general, the physiological variables were those set
out in section 12.3. Table 12.2 summarizes some of
the key variables. The whole oxygen transport system
was modeled using numerical procedures previously
described (West and Wagner 1977, 1980).
Figure 12.8 shows the calculated changes in the P02
of alveolar gas, arterial blood, and mixed venous
blood as the oxygen uptake is increased for a climber
on the summit of Mount Everest. For clarity, a maximum membrane oxygen diffusing capacity of
100 mL min"1 mm Hg-1 has been used for all values of
oxygen uptake, though in practice the diffusing
capacity would presumably be smaller at the lower
work levels. Note the relentless fall in the P02 of the
arterial and mixed venous bloods as the oxygen
demand is increased. The decrease in arterial P02 in
the face of a constant or rising alveolar P02 is the hallmark of diffusion-limited oxygen transfer. The slight
rise in alveolar P02 at low work levels reflects the
assumed increase in respiratory exchange ratio (R)
from 0.8 at rest to 1.0 on moderate exercise.
To calculate maximal oxygen uptake (t)2max) it
was assumed that the P02 of mixed venous blood
could not fall below 15 mm Hg. As discussed in section 12.3.7, direct measurements of the P02 of mixed
Table 12.2 Key variables for analysis factors limiting
oxygen uptake on the summit of Mount Everest

Figure 12.7

Hydraulic analogy to clarify the concept of limitation

of oxygen transfer. Each part of the pipe limits the flow of water to
some extent. However, the extent of the limitation can be
determined by noting the change in flow for a given (say 5 per cent)
change in diameter (D) at a particular point. P is pressure at turbine.

Barometric pressure
Alveolar PC02
Hemoglobin concentration
P50 at pH 7.4
Base excess

253 mm Hg
7.5 mm Hg
18.4gdL-1
29.6 mm Hg
-7.2 mmol L~1

Respiratory exchange ratio

Cardiac output/oxygen uptake
Maximal DM02a
Capillary transit time

1.0
Same as sea level
100 ml min-1 mm Hg~'

0.75s

DM0 diffusing capacity of the membrane for oxygen.

154 Limiting factors at extreme altitude

Figure 12.9 Sensitivity of calculated maximal oxygen

consumption (V02mJ to changes in variables for a climber on the
summit of Mount Everest. The initial conditions are those shown in
Table 12.2, and each variable was increased by 5 per cent leaving
all the others constant. See text for details. (From West 1983.)

Figure 12.8 Predicted changes in the P<,2 of alveolar gas and

arterial and mixed venous blood as oxygen uptake is increased for a
climber on the summit of Mount Everest. It is assumed that \2mm
will occur when ?02 of venous blood falls to 15 mm Hg. Lower values
of venous P0s may allow higher values o/V02. (From West 1983.)

venous blood during Operation Everest II support

this assumption. The calculated \o2max shown in
Figure 12.9 of just over 1 L min"1 agrees well with
results obtained on the AMREE when well acclimatized subjects performed maximal exercise with an
inspired PO2 of 42.5 mm Hg, equivalent to that on the
Everest summit (West et al. 1983c). In addition,
essentially the same value for V0 max was reported by
Sutton et al. (1988) in their measurements during
Operation Everest II when the subjects had an
inspired P02 of 43 mm Hg.
Figure 12.9 shows the sensitivity of \>2max to the
variables in this theoretical study using the type of
analysis shown in Figure 12.7. Note that the calculated t^2max is exquisitely sensitive to barometric
pressure, a 5 per cent increase in this variable resulting in a 25 per cent increase in t^2max when all the
other variables were held constant. This is the basis
for the assertion made in section 12.3.2 that even
day-by-day variations of barometric pressure at these
extreme altitudes may measurably affect exercise
performance.
Figure 12.9 also shows that t2max is very sensitive

to the level of alveolar ventilation and the magnitude

of the membrane oxygen diffusing capacity. The ventilation is important because any increase raises the
alveolar P0r The diffusing capacity is important
because oxygen transfer under these conditions is
diffusion limited (Chapter 6).
An increase in base excess results in a small rise in
calculated t&2max. The reason is that for a given level
of ventilation, and therefore arterial PC02, a rise in
base excess causes an increase in pH which moves the
oxygen dissociation curve further to the left and
increases the oxygen affinity of the hemoglobin. This
assists in the loading of oxygen in the pulmonary
capillaries (section 6.3.7).
By the same token, an increase in P50 of the oxygen
dissociation curve reduces the calculated Vo2max. The
reason is the same: a reduced oxygen affinity of
hemoglobin slows down the loading of oxygen in the
pulmonary capillaries. This is an interesting point
because it has often been claimed that the increase in
2,3-diphosphoglycerate (2,3-DPG) which is seen in
the red cells at high altitude is a useful feature of
acclimatization (Lenfant et al. 1971). In this analysis,
increases of cardiac output and hemoglobin also
improve the t>2max. However, in another theoretical
analysis which takes account of diffusion limitation
of oxygen transfer in the exercising muscles, this
improvement is not seen (Figure 7.5). In fact, in
practice, as discussed in Chapter 6, the relationship

What limits exercise performance at extreme altitude? 155

between cardiac output and t,2max in acclimatized

subjects at high altitude appears to be the same as at
sea level. The chief conclusions from the analysis
shown in Figure 12.9 are as follows:
A climber attempting an ascent of Mount Everest
without supplementary oxygen should ideally
choose a day with a relatively high barometric
pressure. Indeed, this appears to be the most critical variable. Fortunately, climbers generally try to
make a summit assault when the weather is fine
and usually this means a high pressure. Note,
however, that this factor makes a winter ascent of
Mount Everest without supplementary oxygen
particularly difficult.
The climber should not have a low hypoxic ventilatory response because this is critical in maintaining an adequate alveolar P0r
It is advantageous to have a high oxygen diffusing
capacity at a moderate work level.
The climber should have as high a base excess as
possible. Presumably one way to ensure this is to
avoid prolonged stays at extreme altitudes.
Any rise in the level of 2,3-DPG in the red cell is
apparently a liability because it increases the P50
and interferes with the loading of oxygen by the
pulmonary capillaries.

12*43 How high can humans climb

without supplementary oxygen?
We have seen that the X)2max in acclimatized subjects
with an inspired P02 of 43 mm Hg, equivalent to that
on the Everest summit, is only a little over 1 L min~'.
This oxygen uptake is equivalent to walking slowly
on level ground. Clearly, humans at the highest point
on Earth are very close to the limit of hypoxic tolerance.
Nevertheless, it is interesting to speculate on how
much higher humans could climb wihtout supplementary oxygen. The answer from Figure 12.8 seems
to be very little. For example, only a 5 per cent
decrease in barometric pressure from 253 to
240 mmHg is calculated to reduce the V02m3x by
25 per cent, or to less than 800 ml mnr1. This would
occur at an altitude of about 9250 m at the latitude of
Everest, that is 400 m above the summit. Note also
that the pressure of 240 mm Hg is still above that
predicted for the summit of Mount Everest by the
standard atmosphere (Chapter 2), indicating again
that it is only the equatorial bulge in barometric pressure (Figures 2.3 and 2.5) which allows humans to
reach the highest mountain top without supplementary oxygen.

13
Sleep
13.1 Introduction
13.2 Historical
13.3 Physiology of sleep

156
157
158

SUMMARY
Sleep is very commonly impaired at high altitude.
Typically, people complain that they wake frequently,
have unpleasant dreams and do not feel refreshed in
the morning. Polysomnographic studies confirm the
increased frequency of arousals. Electrencephalograms show changes in the architecture of sleep, with
a great reduction in time spent in rapid eye movement (REM) sleep. Periodic breathing is almost
universal at high altitude, and is accompanied by
apneic periods which maybe as much as 10-15 s long.
The mechanism of the periodic breathing may be
related to the strong hypoxic ventilatory drive. High
altitude natives who have a blunted ventilatory
response to hypoxia show less or no periodic breathing compared with lowlanders at high altitude. The
severe arterial hypoxemia which follows the long
apneic periods may reduce the arterial P02 to its
lowest levels of the 24-h period. Acetazolamide stimulates ventilation at high altitude, reduces the time
spent in periodic breathing and improves the arterial
oxygen saturation during sleep. Oxygen enrichment
of room air at high altitude results in fewer apneas,
less time spent in periodic breathing and an improved
subjective assessment of sleep quality.
13.1

INTRODUCTION

Everyone who has been to high altitude knows that

sleeping is often impaired. This ubiquitous problem

13.4 Characteristics of sleep at high altitude

159

13.5 Periodic breathing

160

affects the skier or trekker who sleeps at altitudes of

2500-3000 m, as well as the well acclimatized climber
who spends a night as high as 8000 m. The altitude of
many modern skiing resorts is over 2700 m and
many people who move rapidly from sea level to that
altitude have difficulties with sleep for the first 2 or 3
nights. Often they cannot get to sleep for a long
period, or they wake frequently, and often they complain that they do not awake refreshed in the morning. This last comment is also frequently heard from
climbers at great altitudes on expeditions (Pugh and
Ward 1956). Some people trying to sleep at high altitude complain that the mind races with a kaleidoscope of thoughts tumbling through it; this is
certainly the case with the writer, who recognizes this
as a very characteristic feature of the first night or
two at high altitude.
Climbers at high altitude are often urged to climb
high during the day but sleep low during the night.
This advice acknowledges the increased incidence of
difficulties during sleep. Many climbers over an
altitude of about 7000 m find that a very low flow of
supplementary oxygen of perhaps 1 L min"1 greatly
improves the quality of sleep.
Periodic breathing during sleep at high altitude
has been recognized since the nineteenth century. It
is extremely common and may pose a hazard at
extreme altitude because of the severe arterial
hypoxemia which follows the apneic periods (West et
al. 1986). Indeed, this maybe one of the factors that
influences tolerance to very great altitudes. From a
scientific point of view, periodic breathing during

Historical 157

sleep at high altitude throws light on the control of

breathing under these special conditions.
The present chapter overlaps the material of
Chapter 5 on the control of ventilation, and also has
some links with Chapter 7 on cardiovascular
responses because of the alterations in heart rate that
occur with periodic breathing.

13.2
13.2*1

HISTORICAL
Quality of sleep

There have been a number of anecdotal references to

the poor quality of sleep at high altitude. A particularly colorful description was given by Barcroft when
he recounted his experiences during the glass
chamber experiment carried out at Cambridge
(Barcroft et al. 1920). On that occasion he spent
6 days in a closed chamber in which the concentration of oxygen was regulated so that the initial
equivalent altitude was 10 000 ft (3048 m) and the
final altitude 16 000 ft (4877 m). He wrote:
In the glass case experiment I had the opportunity of judging a little more exactly of anoxaemic
sleeplessness than is usually the case. A committee of undergraduate pupils of mine made up
their minds that I was never to be left alone, two
of them therefore sat up each night outside the
case lest help of any sort should be required. I
used to ask them in the morning how I had slept,
and each morning except perhaps the last they
said I had slept well. My own view of the matter
was quite otherwise. I thought I had been awake
half the night and was unrefreshed in the morning. I was conscious of their moving about and
looking in through the glass to see whether or not
I was awake. I used to count my pulse at
intervals. The two opinions can only be reconciled
on the hypothesis that whilst I spent most of the
night in sleep, the slumber was very light and
fitful with incessant dreams. Even some low
degree of consciousness which fell short of wakefulness. At Cerro it was the same: measured in
hours we slept well, but the quality of the sleep
in most cases was of an inferior order. The night
seemed long and we woke unrefreshed (Barcroft
1925, p. 166).

13.2.2

Periodic breathing

Various references to the uneven pattern of breathing during sleep at high altitude were made during
the nineteenth century. One was by the eminent
English physicist Tyndall who was one of the most
ardent Alpine mountaineers in the middle of the century. Paul Bert commented that 'every year sees him
planting his alpenstock on some new summit' (Bert
1878). During Tyndall's first ascent of Mont Blanc in
1857, he became very fatigued. 'I stretched myself
upon a composite couch of snow and granite, and
immediately fell asleep. My friend, however, soon
aroused me "You quite frighten me" he said, "I
listened for some minutes and have not heard you
breathe once".' On renewing the ascent, Tyndall
complained of palpitations. 'At each pause my heart
throbbed audibly, as I leaned upon my staff, and the
subsidence of this action was always the signal for
further advance' (Tyndall 1860).
Another early comment on periodic breathing was
made by Egli-Sinclair (1894) in an article on
mountain sickness. He noted that, at an altitude of
4400 m, respiration 'had the Stokes character, that is,
it seemed regular during a certain time, after which a
few rapid and profound breaths were drawn, a total
suspension of a few seconds then following.' Here he
was referring to the Irish physician, Dr. William
Stokes, who described the pattern of breathing which
'consists in the occurrence of a series of inspirations,
increasing to a maximum and then declining in force
and length until a state of apparent apnoea is
established' (Stokes 1854). Another Irish physician,
John Cheyne, had described the same pattern in 1818
(Cheyne 1818) and so the breathing pattern is often
known as Cheyne-Stokes breathing. However, Ward
(1973) pointed out that John Hunter had given a
lucid and succinct description of the same condition
in 1781 (Hunter 1781).
The first extensive studies of periodic breathing at
high altitude were made by Angelo Mosso, Professor
of Physiology at the University of Turin, Italy. As
mentioned earlier, he was one of the first people to
use the Capanna Regina Margherita on the Monte
Rosa at an altitude of 4559 m for scientific work. He
measured the breathing movements by means of a
lever which rested on the chest. An example of one
of his measurements on his brother, Ugolino
Mosso, is shown in Figure 13.la. The periods of
apnea lasted about 12 s. Note that in this instance,

158 Sleep

Figure 13.1 Earliest tracings showing

periodic breathing at an altitude of
4560 m: (a) a record from Ugolino Mosso,
brother of Angela Mosso. Note the apneic
periods of approximately 72 s; (b) a tracing
from Francioli, keeper of the Regina
Margherita hut. Note the waxing and
waning of respiration. (From Mosso 1898.)

the first breath after the apneic period was the

largest. A more typical pattern is that shown in
Figure 13.Ib which was measured on Francioli,
keeper of the Regina Margherita hut. In this
instance the waxing and waning of breathing movements are clearly seen and the periods of apnea are
shorter (Mosso 1898, pp. 42-7).
A curious feature of Mosso's measurements was
that he concluded that ventilation was actually
decreased at high altitude, apparently because he
converted his readings to standard conditions (0 C
and 1000 mm Hg in his case) rather than BTPS (body
temperature and pressure saturated). Interestingly,
Paul Bert also believed that hyperventilation did not
occur at high altitude (Bert 1878, p. 106 in the 1943
translation). He wrote, 'What is really certain is that
... a dweller in lofty altitudes, does not even try to
struggle against the decrease of oxygen in his arterial
blood by speeding up his respirations excessively, as
was first supposed. The observations of Dr.
Jourdanet are conclusive.' Bert probably reached this
conclusion because he worked exclusively with low
pressure chambers that only allowed short-term
observations. It was not until Mosso could work in
the Capanna Regina Margherita a few years later that
measurements were easily made on subjects exposed
to high altitude for several days although, as
indicated above, he thought that ventilation was
decreased.
Mosso realized that the alveolar PC02 was reduced
in people living in the Capanna Regina Margherita at
4559 m, but instead of attributing this to an
increased ventilation, he argued that the low pressure
at high altitude extracted carbon dioxide from the
blood just as does a mercury pump in a blood-gas
analysis apparatus. Barcroft (1925) could not follow

Mosso's argument and remarked: 'I speak with all

deference, but Mosso seems to me to have overlooked the fact that the body is exposed to what is
practically a vacuum of carbon dioxide, whether it be
at the Capanna Margherita or in his own laboratory
at Turin.' Mosso introduced the term 'acapnia' to
refer to the reduction of Pcc>2 and believed that this
was an important factor in the development of acute
mountain sickness (AMS). Indeed, it may well be
that the symptoms of this condition are related in
part to the respiratory alkalosis. However, Barcroft
(1925) pointed out that Mosso's theory was not
supported by the experience at the Alta Vista hut
(3350 m) on Tenerife during the First International
High Altitude Expedition of 1910. Barcroft had an
almost normal alveolar Pcc,2 (38 mmHg) but was
incapacitated by the altitude, whereas Douglas,
whose PC02 was only 32 mm Hg, was 'perfectly free
from all symptoms'. Thus hypoxia (which was more
severe in Barcroft because he did not increase his
ventilation) rather than the low PC02 was implicated
in the etiology of mountain sickness.

133

PHYSIOLOGY OF SLEEP

Despite the fact that we spend up to one-third of our

lives in the sleeping state, the physiology is not completely understood. Sleep can be defined as a state of
unconsciousness from which the subject can be
aroused by sensory or other stimuli. As such it can be
distinguished from deep anesthesia and diseased
states which cause coma, though these have some
features in common with true sleep.
Two major types of sleep are recognized.

Characteristics of sleep at high altitude 159

133.1

Slow wave sleep (SWS)

This is often called non-REM or NREM sleep, or

sometimes normal sleep. It is characterized by
decreased activity of the reticular activating system,
and is called slow wave sleep (SWS) because of the
predominance of slow delta waves in the electroencephalogram (EEC). These slow waves have a high
voltage and occur at a rate of 1 or 2 s~l. In the early
stages of sleep, the alpha rhythm (8-13 Hz), which is
always present during wakefulness, becomes more
obvious. In addition, sleep spindles (14-16 Hz) may
appear. These features can be used to divide SWS
into four stages (I-IV). The delta waves probably
originate in the cortex of the brain when it is not
driven from below because of the reduced level of
activity of the reticular activating system. SWS is
dreamless, very restful and associated with a
decreased peripheral vascular tone, blood pressure,
respiratory rate and basal metabolic rate.
13.3*2

Paradoxical or REM sleep

This is called REM sleep because, although the eyes

remain closed, there are rapid horizontal eye movements. In a normal night of sleep, bouts of REM
sleep lasting 5-20 min usually appear on the average
about every 90 min. Often the first such period
occurs 80-100 min after the subject falls asleep. The
EEC tracing resembles the waking state, but the
person is actually more difficult to arouse than
during NREM sleep. REM sleep is usually associated
with active dreaming; the muscle tone throughout
the body is greatly depressed, but there may be
occasional muscular twitching and limb jerking. The
heart rate and respiration usually become irregular.
Thus, in this type of sleep, the brain is quite active
but the activity is not channeled in the proper direction for the person to be aware of his or her surroundings.
In experimental animals, sleep can be produced by
electrically stimulating the raphe nuclei in the pons
and medulla. There are extensive nerve fiber connections between these nuclei and the reticular
formation. These nerve fibers secrete serotonin and
some physiologists believe that this is a major transmitter substance associated with the production of
sleep. However, other possible transmitter substances may play a role in the onset of sleep.

Sleep deprivation impairs mental function, the

higher brain functions being the most susceptible.
There are similarities between the behavior of sleepdeprived subjects and people at high altitude whose
brains are affected by hypoxia. In both instances, mental activities which are 'mechanical' in nature, such as
tabulating a set of data, can be accurately accomplished, whereas activities that require problem solving and initiative are seriously affected (Chapter 16). It
maybe that some of the impairment of CNS function
in individuals living at high altitude can be ascribed to
the poor quality of sleep, but the direct effects of
hypoxia on the brain also clearly play a role.

13.4
CHARACTERISTICS OF SLEEP AT
HIGH ALTITUDE
13.4.1

Increased frequency of arousals

People at high altitude often report that they wake

more frequently during the night than at sea level,
and this has been confirmed by careful studies (Reite
etal. 1975, Weil etal 1978,Salvaggioef al 1998). The
subjects had continuous recordings of the EEC,
electromyogram (EMG) and eye movements, and an
arousal was recognized by the occurrence of EMG
activation, eye movements and alpha wave activity
on the EEC. In one study an average of 36 arousals
per night occurred at an altitude of 4300 m
compared with 20 at sea level (Weil et al. 1978).
Administration of the drug acetazolamide, which is
known to stimulate ventilation at high altitude,
reduced the frequency of arousals.
Some investigators believe that the arousals are
caused in some way by periodic breathing. There is
some evidence that arousals are more frequent when
the strength of periodic breathing is high. It is easy to
imagine that the strenuous muscular activity
required to generate large breaths after a prolonged
period of apnea could contribute to an arousal. A
common nightmare at high altitude is that the tent
has been covered with snow by an avalanche and the
subject wakes violently feeling suffocated and very
short of breath. This may be associated with the air
hunger caused by a long apneic period as part of
periodic breathing. However, arousals are more
frequent at high altitude, even in individuals who do
not have periodic breathing (Reite etal. 1975).

160 Sleep

13*4.2

Changes of sleep state

EEC studies confirm that there is a deterioration in

the quality of sleep at high altitude. Light sleep
(stages I and II of NREM) is increased, whereas there
are decreases both in deep sleep (stages III and IV of
NREM) and in REM sleep. In some studies, REM
sleep is virtually abolished (Pappenheimer 1977,
Megirian et al. 1980). These studies of the electrical
activity of the brain support the subjective conclusions of climbers that sleep at high altitude is often
of poor quality, and not as refreshing as sleep at sea
level.
Studies on rats by Pappenheimer (1977, 1984)
have clarified the alterations in sleep at high altitude.
In one study rats were exposed to 10 per cent oxygen,
equivalent to an altitude of approximately 5490 m.
The proportion of time spent in slow wave (NREM)
sleep was measured from EEC recordings via
chronically implanted cortical electrodes. Rats
typically sleep on and off during the day, and during
this period the proportion of time spent in SWS was
45 per cent when the rats breathed air, but only
27 per cent when they breathed the low oxygen mixture. Adding carbon dioxide to the inspired gas failed
to prevent the reduction of SWS during hypoxia.
This indicated that the effects of hypoxia on sleep
depended on the changes in P0l rather than on the
changes in PC02.
The effect of sleep and hypoxia on the pattern of
breathing was also studied. SWS decreased breathing
frequency and minute volume by 10-20 per cent.
However, when the animals inhaled the hypoxic
mixture, the frequency increased markedly when the
animals entered SWS, though the minute volume
was not significantly changed. It was concluded that
stimulation of breathing by hypoxia was greater during SWS than during wakefulness.
In a subsequent study (Pappenheimer 1984), the
amplitudes of the cortical slow waves were measured
during NREM sleep, and the relative amounts of
REM and NREM sleep were also assessed. It was
found that acute exposure of rats to 10.5 per cent
oxygen (5030 m altitude equivalent) during daylight
hours virtually abolished REM sleep. In addition, the
distribution of amplitudes of the EEC of SWS shifted
towards the values seen in awake animals. Adding
carbon monoxide to the inspired gas sufficient to
increase the concentration of carboxyhemoglobin to
35 per cent did not alter respiration rate and alveolar

ventilation. It was therefore inferred that hypoxic

stimulation of sleep was not mediated by peripheral
chemoreceptors regulating breathing.
Pappenheimer also measured the amplitude of the
cortical slow waves during sleep and showed that this
was greatly reduced at the simulated high altitude
(Figure 13.2). In fact, the primary effects of hypoxia
were to reduce the amplitude of the EEC slow waves,
and to shift the distribution of amplitudes towards
the awake values, as shown in Figure 13.2.
Pappenheimer suggested that this reduction in
amplitude reflected the poor quality of the NREM
sleep. In other words, even if the duration of NREM
sleep as determined by conventional EEC recordings
is not greatly reduced at high altitude, the quality of
the NREM sleep may be greatly impaired. This conclusion fits with the assessments of the poor quality
of sleep at high altitude given by many climbers, and
Barcroft's colorful description quoted in section
13.2.1.

Figure 13.2 Effects of acute hypoxia on the EEG pattern of

sleeping rats. The ordinate shows the product of EEG amplitude
and time. Hypoxia shifts the distribution of slow waves to lower
amplitudes (light sleep), and reduces the amount of both NREM
and REM sleep. (From Pappenheimer 1984.)

13.5
13.5.1

PERIODIC BREATHING
Characteristics

Early records of chest movements during periodic

breathing are shown in Figure 13.1. This pattern has

Periodic breathing 161

Figure 133 Example of

periodic breathing at altitude
6300 m (PB 351 mm Hg). (From
West etal. 1986.)

now been confirmed in many studies carried out at

various altitudes from sea level up to 8050m
(Douglas and Haldane 1909, Douglas et al. 1913,
Weil etal 1978, Sutton et al 1979, Berssenbrugge et
al. 1983, Lahiri etal. 1983, West etal. 1986).
A typical pattern recorded at an altitude of 6300 m
(PB 351 mmHg) in a well acclimatized lowlander
using modern equipment is shown in Figure 13.3
(West et al. 1986). Note that the tidal volume waxed
and waned during each burst of breathing, with
apneic periods of about 8 s. Arterial oxygen saturation as measured by ear oximeter fluctuated with the
same frequency as the periodic breathing. Note the

phase difference; the highest arterial oxygen

saturation (inverted scale) occurred at approximately the end of the apneic period. This can be
accounted for by the circulation time from the lung
capillaries to the ear where the oxygen saturation was
measured. Heart rate was measured from the electrocardiogram (EGG) and showed marked fluctuations
with the same frequency as the periodic breathing.
Note that the highest heart rate appeared at the end
of the burst of ventilation.
Nocturnal periodic breathing is extremely
common in lowlanders who ascend to high altitude.
In the study from which Figure 13.3 is taken, all eight

Table 13.1 Features of periodic breathing at 6300 m altitude

RP

25

DG
CP

30

94
97

31

62

DK
PH
DJ
FS
JM
Mean

SD

85.3

80

61.3

12.5

61

90.0

33
33
33
38
51

133
170
210
138
123

71.3
57.2
77.7
76.1
61.0

34.3
7.7

128

72.5

46

12.0

2.6
17.7
13.2
15.8
5.5
15.3
10.3
6.7

Source: West etal. (1986).

Apneic periods were only seen in a small proportion of cycles in this subject.

59

17.9
23.4
19.5

7.5

0.42

8.8

0.38
a

0.36

7.0

78

19.7

0.40

7.9

54
66
84

0.38
0.38
0.40

79

20.1
24.3
21.4
17.7

0.35

7.6
9.2
8.6
6.2

70.1
11.4

20.5
2.4

0.38
0.02

1.0

7.9

162 Sleep

subjects who were living at an altitude of 6300 m

showed obvious periodic breathing during the several
weeks over which the measurements were made.
Table 13.1 shows some of the features of periodic
breathing during this study. Measurements were
made over a period of about 1-3.5 h late at night and
the proportion of the study period during which
periodic breathing was seen varied between 57 per
cent and 90 per cent. In general, the percentage of
time occupied by periodic breathing increases with
altitude. For example, Waggener et al. (1984)
reported that periodic breathing with apnea
occupied 24 per cent of the time at 2440 m, and that
the percentage increased to 40 per cent at 4270 m.
This increase in proportion of time is consistent with
a theoretical model discussed below (Khoo et al.
1982) and with the fact that periodic breathing is

Figure 13.4 Variation of cycle time of periodic breathing with

altitude. Points marked 'Previous data' were originally published
as Figure 8 in the paper by Khoo et al. (1982), the solid line being
results predicted by their model (%). Vertical broken lines indicate
differences caused by scaling between neonates and adults. For
sources of data see Khoo et al. (1982). 'This study' refers to West et
al. (1986). (From Westet al. 1986.)

occasionally observed during sleep at sea level but the

proportion of time spent in periodic breathing is
small (Priban 1963, Goodman 1964, Lenfant 1967).
In the American Medical Research Expedition to
Mount Everest (AMREE) study from which Figure
13.3 is taken, we were not able to determine how
much of the time the subjects were actually asleep.
However, other studies have shown that periodic
breathing is very common during NREM sleep at
high altitude, but that it is uncommon during REM
periods (Reite etal. 1975, Berssenbrugge etal. 1983).
Of course, as indicated above, REM sleep itself is
uncommon at high altitude.
Table 13.1 shows that the duration of the periodic
breathing cycle had a mean of 20.5 s. This was the
same as the cycle length measured in a companion
study at 5400 m (Lahiri et al. 1983). There is evidence
that cycle length decreases with increasing altitude
(Waggener et al. 1984) and studies at sea level indicate a cycle period of about 30 s (Douglas and
Haldane 1909, Specht and Fruhmann 1972, Lugaresi
et al. 1978). Figure 13.4 shows a plot of cycle time
against altitude for several experimental studies and
the theoretical model developed by Khoo et al.
(1982). It can be seen that the cycle times from the
AMREE studies were somewhat greater than
predicted by the model.
There is evidence that the apneic periods are of
central nervous origin rather than being caused by
airway obstruction. This is supported by the absence
of rib cage and abdominal movements as determined
from an inductance plethysmograph, a device used
for detecting changes in circumference of the chest
and abdomen. There was no evidence that the
percentage of time during which periodic breathing
was observed was altered by the duration of acclimatization. All subjects showed obvious periodic
breathing but all were well acclimatized.

Figure 13.5 Cyclic variation of

heart rate caused by periodic
breathing in a climber at 8050 m
altitude. PB - 282 mm Hg. (From
West et al. 1986.)

Periodic breathing 163

Changes of heart rate during the periodic breathing cycle were seen in all subjects and Figure 13.3 is a
good example. In general, the maximum heart rate
appeared shortly after the peak of the hyperpnea.
Cardiac rhythm abnormalities were infrequent. In
one subject, ventricular premature contractions
occurred mainly during the apneic periods. However, this subject had a history of occasional
ventricular premature contractions at sea level.
There were no other observable changes in EGG
pattern except for minor alterations that could be
attributed to changes in the position of the heart
caused by breathing movements.
In four subjects, evidence of periodic breathing
was obtained at an altitude of 8050 m (PB
282 mm Hg). In these studies, breathing movements
were not recorded directly because of the very
remote location of the camp. However, continuous
EGG tracings were obtained during the night using a
Holter-type monitor, and the occurrence of periodic
breathing was inferred from the variations in heart
rate as described by Guilleminault et al. (1984). An
example is shown in Figure 13.5. This particular
subject showed extremely regular cyclic regulation of
heart rate over long periods of time (up to 40 min). It
was easy to distinguish between this type of cyclic
variation caused by periodic breathing and sinus
arrhythmia.

13*5.2

Control of breathing

The control of breathing during sleep has been

extensively studied: for a review see Phillipson et al.
(1978). The ventilatery response to carbon dioxide is
reduced, at least in NREM sleep (Bulow 1963).
However, there is more uncertainty about the

hypoxic ventilatory response; some studies indicate

that it is increased in NREM sleep (Pappenheimer
1977, Phillipson et al 1978). Responses to
pulmonary stretch receptor stimulation appear to be
intact during NREM sleep but may be decreased in
REM sleep (Phillipson etal. 1978).
The control of ventilation during hypoxic sleep
has been less well studied and there are many unanswered questions (Dempsey 1983). Lahiri et al.
(1983) studied the role of added oxygen and carbon
dioxide, and the importance of the hypoxic ventilatory response to periodic breathing in both well
acclimatized lowlanders and native Sherpas at an
altitude of 5400 m.
Figure 13.6 shows the effect of adding oxygen to
the inspired air. It can be seen that there was an
immediate increase in the apneic period from
about 10s to 17s. Subsequently, the apneic period
shortened and shallow rhythmic breathing resumed
as the arterial PC02 increased because of the fall in
alveolar ventilation. In most subjects, the periodicity of breathing did not totally disappear following
the addition of oxygen, but the strength of the periodic breathing was clearly greatly diminished. The
changes can be partly explained by the reduction in
respiratory drive from the peripheral chemoreceptors when the arterial P02 was raised.
Adding carbon dioxide to the inspired gas did not
abolish the periodic breathing, although it did
eliminate the periods of apnea. Withdrawal of
carbon dioxide from the inspired air was followed by
a prompt reappearance of apnea, and the rapidity of
the response suggested a dominant role for the
peripheral chemoreceptors.
An important finding was that, although the
lowlanders showed marked periodic breathing at
5400 m, the Sherpas generally did not. The only

Figure 13.6 Effect of increasing

the inspired P02 on periodic
breathing in a lowlander during
sleep at 5400 m. Note that adding
oxygen to the inspired gas raised
the arterial oxygen saturation,
eliminated the apneic periods, and
reduced the strength of periodic
breathing. V7, tidal volume; Sa02,
arterial oxygen saturation; E,
expiration, I, inspiration. (From
Lahiri and Barnard 1983.)

164 Sleep

Figure 13.7 Relationship between frequency of sleep apnea and

ventilatory response to hypoxia (awake). , acclimatized
lowlanders; A, high altitude Sherpas; A, lower altitude Sherpa.
One lowlander did not have periods of apnea, and the low altitude
Sherpa showed periodic breathing. (From Lahiri et a I. 1983.)

exception was one Sherpa who had spent long

periods of time at low altitudes. As discussed in
Chapter 5, the Sherpas generally show low ventilatory responses to hypoxia, although the low
altitude Sherpa had an intermediate value. Figure
13.7 shows the relationship between the frequency of
apnea during sleep at 5400 m and the hypoxic
ventilatory response. It is clear that a high hypoxic
ventilatory response predisposes to periodic
breathing.

13.53

Mechanism

It is profitable to discuss the mechanism of periodic

breathing in terms of control theory, and a particularly useful analysis was presented by Khoo et al.
(1982). They pointed out that two factors are necessary for self-sustained oscillatory behavior in a
control system. In such a system we can identify a
'disturbance', for example a change in alveolar
ventilation caused by some adventitious factor such
as a sigh or alteration of body position. This is
followed by a 'corrective action' which tends to
suppress the disturbance. In the case of an increase in
alveolar ventilation (caused by a sigh, for example)
the corrective action would be a lowering of -PCo2>
which would tend to reduce ventilation by its action
on central and peripheral chemoreceptors and thus

constitute negative feedback. The first necessary

requirement for sustained oscillatory behavior is that
the magnitude of the corrective action exceeds that
of the disturbance, this ratio being known as the loop
gain.
The second necessary condition is that the
corrective action be presented 180 out of phase with
the disturbance, so that what would otherwise inhibit
the change in ventilation now augments it. This
sustained oscillatory behavior occurs when the loop
gain exceeds unity at a phase difference of 180.
This theory predicts that the higher the loop gain
at a phase angle of 180, the more likely periodic
breathing is to occur, the more marked the pattern of
periodic breathing, and the shorter the cycle length
of the periodic breathing. The main factor increasing
loop gain in acclimatized lowlanders at high altitude
is the increased chemoreceptor gain, particularly the
response to severe hypoxia (Chapter 5). Other
contributing factors may be the hyperventilation,
which increases the rate of wash out of carbon
dioxide and wash in of oxygen in the lungs, and the
reduction of functional residual capacity in supine
subjects.
This analysis explains why there is a difference
between acclimatized lowlanders and Sherpas in
periodic breathing. Because native highlanders have
a blunted hypoxic ventilatory response (Severinghaus et al. 1966a, Milledge and Lahiri 1967), the loop
gain of the control system is reduced and the factors
promoting periodicity are weak. Lahiri et al. (1983)
have argued that this represents an important feature
of the true adaptation of native highlanders such as
Sherpas to high altitude. Periodic breathing is disadvantageous because of the very low levels of
arterial P0z following the apneic periods (section
13.5.4). In addition, the reduced ventilation at high
altitude lowers the oxygen cost of ventilation.
In the analysis discussed above, a disturbance, for
example an arousal, is postulated to play an
important role in the genesis of periodic breathing.
However, Khoo et al. (1996) looked at the relationship between arousals and the initiation of periodic
breathing in healthy volunteers at simulated altitudes
of 4572, 6100 and 7620 m. They found that although
arousals promoted the development of periodic
breathing with apnea in some instances, arousals
were not necessary for the initiation of periodic
breathing in all circumstances.
In another study of periodic breathing at high

Periodic breathing 165

altitude, measurements were made on nine Japanese

climbers who participated in an expedition to the
Kunlun mountains (7167 m) in China (Matsuyama
et al. 1989). There was a significant correlation
between the degree of periodic breathing during
sleep and both the hypoxic ventilatory response and
hypercapnic ventilatory response measured at sea
level (p < 0.05). Although all climbers showed desaturation during sleep, there was a negative correlation
between the degree of desaturation and the hypoxic
ventilation response (HVR) (p < 0.05). The authors
concluded that the high HVR helped to maintain the
arterial oxygenation during sleep, and that it was
therefore advantageous.
In a further study, subjects with early high altitude
pulmonary edema (RAPE) showed a trend towards
more periodic breathing than subjects without
HAPE, probably because of lower values of arterial
oxygen saturation (Eichenberger et al. 1996). In a
study of patients with chronic mountain sickness at
3658 m altitude, sleep-disordered breathing was
more common than in a control group (Sun et al.
1996).

13.5*4

Gas exchange

Periodic breathing causes marked fluctuations in the

arterial P02 which is not surprising considering the
long periods of apnea that sometimes occur. Figure
13.3 shows a typical record of fluctuations in arterial
oxygen saturation as recorded by ear oximeter.
Another example is seen in Figure 13.6.
In the study of nocturnal periodic breathing
carried out at an altitude of 6300 m during the 1981
AMREE, the mean fluctuation in arterial oxygen
saturation between subjects was approximately
10 per cent (West et al. 1986). In order to determine
the proportion of the time during which the arterial
oxygen saturation fell below a particular value, the
analysis described by Slutsky and Strohl (1980) was
carried out. This showed that the arterial oxygen
saturation below which the subjects spent 50 per cent
of their time varied from a minimal value of
64.5 per cent to a maximum of 74.5 per cent with a
mean of 68.8 per cent.
Since it is not usually feasible to sample arterial
blood over prolonged periods of time, most investigators of periodic breathing have relied on the
arterial oxygen saturation measured by ear oximetry.

However, based on spot measurements of arterial P02

it was calculated that the maximum and minimum
values of saturation of 73.0 per cent and 63.4 per cent
from the AMREE study corresponded to arterial P02
values of approximately 39 and 33 mmHg
respectively. The conclusion was that the minimal
arterial P02 during sleep was approximately 6 mm Hg
lower than the resting daytime value, a substantial
difference on this very steep part of the oxygen
dissociation curve. It should be pointed out that, at
high work rates, the arterial P02 falls considerably
below the resting value. However, climbers during
their normal activity do not generally work at more
than two-thirds of their maximal power (Pugh 1958;
section 11.9) so it was concluded that the most severe
arterial hypoxemia over the course of the 24 h
probably occurred during sleep as a result of the
periodic breathing.
Another factor which may exaggerate the effects of
this arterial hypoxemia is the augmented cardiac
output during the periods when the arterial P02 is
near its lowest value. As Figures 13.3 and 13.6 show,
the lowest arterial oxygen saturation typically occurs
just after the peak of ventilation during the periodic
breathing cycle. If venous return and thus cardiac
output are enhanced during this hyperpneic phase,
this would lead to enhanced delivery of this poorly
oxygenated blood. Thus it may be that the phasing of
arterial P02 and cardiac output aggravate the resulting impairment of oxygen delivery.
It is possible that the severe arterial hypoxemia
during periodic breathing affects tolerance to
extreme altitude. This leads to a paradox. As Figure
13.7 shows, there is a correlation between hypoxic
ventilatory response and the strength of the periodic
breathing, as would be expected from the control
theory discussed in section 13.5.3. This would
suggest that climbers with a high hypoxic ventilatory
response would tolerate altitude poorly. However,
the opposite is generally found to be the case
(Schoene et al. 1984; Chapter 5). This can be
explained by the better ability of these climbers to
defend their alveolar P02 against the low inspired
value by hyperventilation (Chapter 12). However, it
is clear that some elite mountain climbers have, in
fact, a relatively low hypoxic ventilatory response
(Milledge etal. 1983c, Schoene etal. 1987). One possible explanation is that these climbers maintain a
higher arterial P02 during the night, and this is a factor in their tolerance to extreme altitude.

166 Sleep

13.5.5

Effects of drugs

Because of the poor quality of sleep at high altitude

and the suspicion that this is sometimes related to
periodic breathing, there has been considerable
interest in the use of drugs to promote a normal
breathing pattern. Sutton et al. (1979) showed that
the administration of acetazolamide at a dose of
250 mg three times per day decreased the time spent
in periodic breathing from 80 per cent to 35 per cent
at an altitude of 5360 m. This was associated with an
improvement in arterial P02 as judged by the arterial
oxygen saturation measured by ear oximetry. Weil et
al. (1978) used acetazolamide at an altitude of
4400 m and found that the duration of periodic
breathing decreased from 35 per cent to 18 per cent.
Hackett et al. (1987a) found a decrease from
41 per cent to 17 per cent at 4400 m in four subjects
with the same drug.
The mode of action of acetazolamide is not fully
understood, but it stimulates ventilation possibly

Figure 13.8 Effects of a placebo, almitrine and acetazolamide

on periodic breathing and arterial oxygen saturation (Sa02) at an
altitude of 4400 m. Note that acetazolamide abolished the apneic
periods whereas almitrine exaggerated them. (From Hackett et al.
1987.)

because it induces a metabolic acidosis. At any event,

its value at high altitude is now generally accepted in
that it reduces the incidence of acute mountain sickness (Hackett and Rennie 1976), maintains a higher
alveolar P02 and lower PC02, and may even prevent
some of the weight loss which normally occurs as a
result of muscle protein breakdown (Birmingham
study 1981).
Almitrine is another drug that stimulates ventilation, apparently through its effect on peripheral
chemoreceptors. It has been shown to improve the
arterial oxygenation of patients with chronic
bronchitis and emphysema during sleep at sea level
(Connaughton et al. 1985). Hackett et al. (1987a)
compared the effects of almitrine and acetazolamide
on the respiratory pattern of four subjects at an
altitude of 4400 m on Mount McKinley in Alaska in
a double-blind, randomized, three-way crossover
trial. Both almitrine and acetazolamide increased the
arterial oxygen saturation during sleep but, whereas
acetazolamide decreased periodic breathing,
almitrine increased it (Figure 13.8). This result is
consistent with the data of Figure 13.7 and the
discussion in section 13.5.3 where it was pointed out
that the strength of periodic breathing is related to
the hypoxic ventilatory response. Since almitrine
increases this response by stimulating peripheral
chemoreceptors, it is not surprising that it exaggerates the periodic breathing. It should also be
pointed out that almitrine tends to increase
pulmonary vascular resistance by enhancing hypoxic
pulmonary vasoconstriction (section 7.5.1), and
since pulmonary hypertension occurs at high
altitude through this mechanism, this is an undesirable side effect. Thus the use of almitrine is probably
contraindicated at high altitude.
Other drugs have also been studied in an attempt
to improve the quality of sleep at high altitude. There
have been several studies of the benzodiazepine
family. Dubowitz (1998) reported that the number
and severity of changes in arterial oxygen saturation
during sleep were decreased, and the quality of sleep
was improved following administration of
temazepam at an altitude of 5300 m. He found no
significant drop in mean oxygen saturation values
during sleep. However, Roggla et al. (1994) found
that low dose sedation with diazepam reduced the
ventilatory response at moderate altitude. In a
subsequent study of temazepam, Roggla et al. (2000)
showed that, at an altitude of 3000 m, the arterial

Periodic breathing 167

ber, Beaumont et al. (1996) reported improved sleep

quality at high altitude without adverse effects on
respiration. Blood gases were not looked at in this
study.
13.5.6 Effect of oxygen enrichment of
room air

Figure 13.9 Comparison of the time spent by 18 subjects in

periodic breathing with apneas during sleep in ambient air,
compared with an atmosphere of 24 per cent oxygen at an altitude
of 3800 m. The paired differences were significant (p < 0.01).
(From Luks et al. 1998.)

PCo2 (determined from earlobe blood) was significantly increased and the arterial P02 significantly
decreased after 10 mg of temazepam.
In a study of zolpidem, an imidazopyridine
hypnotic drug, on sleep and respiratory patterns at a
simulated altitude of 4000 m in a low pressure cham-

Adding oxygen to the ventilation of a room shows

promise as a way of combating the hypoxia of high
altitude, particularly for people who commute to
high altitude to work (see Chapter 29). Luks et al.
(1998) carried out a randomized, double-blind trial
at an altitude of 3800 m to determine whether
oxygen enrichment of room air to 24 per cent at
night improved sleep quality and performance and
well being the following day. They found that, with
oxygen enrichment, the subjects had significantly
fewer apneas and spent significantly less time in
periodic breathing with apneas than when they slept
in ambient air (Figure 13.9). Subjective assessments
of sleep quality were also significantly improved.
There was a lower acute mountain sickness score in
the morning after oxygen-enriched sleep, using the
Lake Louise criteria. Of particular interest, subjects
who slept in the oxygen-enriched atmosphere had a
significantly greater increase in arterial oxygen
saturation from evening to morning compared with
subjects who slept in ambient air. This latter finding
suggested either that the control of breathing may
have been altered by sleeping in an oxygen-enriched
atmosphere, or that there was less subclinical
pulmonary edema.

14
Nutrition and intestinal function
14.1
14.2
14.3
14.4
14.5

Introduction
Energy balance at altitude
Weight loss on altitude expeditions
Body composition and weight loss
Intestinal absorption and hypoxia

168
169
170
172
173

SUMMARY
Loss of appetite and loss of weight are common at
altitude. Initially these maybe due to acute mountain
sickness (AMS). At heights below about 4500 m
appetite returns after a few days but at more extreme
altitudes anorexia persists and may get worse.
Weight loss on an altitude trip can have many causes.
On trek, initial weight loss may be the shedding of
excess fat due to a sedentary lifestyle. Intestinal infections can cause diarrhea and weight loss. High on the
mountain unavailability of food and liquid can be
the cause but even in the absence of these factors
weight loss is seen, as in long-term chamber studies.
In considering energy balance at altitude, basal
metabolic rate is increased 10-17 per cent at
4000-6000 m and possibly more at extreme altitudes.
Exercise increases energy needs, though the reduction in maximum work rate would be expected to
reduce the energy requirement of climbing.
However, the use of new techniques has given values
of energy expenditure when climbing at extreme altitudes that are at least as high as in the Alps, if not
higher. So daily energy needs are high while intake is
often reduced because of anorexia. Recent research
suggests that the cause of this anorexia maybe mediated by the hormone leptin or by cholecystokinin.

14.6
14.7
14.8
14.9

Intestinal permeability
Protein metabolism at altitude
Diet for high altitude
Nutrition and metabolism in high altitude
natives

174
175
175
177

Weight loss results in a change of body composition; fat tends to be lost at low elevations but muscle
at higher altitudes.
Apart from calorie imbalance, there is some evidence that at altitude above about 5500 m there is
malabsorption of food and an increase in intestinal
permeability. This effect of hypoxia on the gut will
increase the weight loss.
Diet is important on treks and expeditions. There
are good physiological reasons to advise a high
carbohydrate, low fat diet and most climbers seem to
favor this. However, palatability is probably more
important than composition in combating the loss of
appetite. Taste is dulled and most find that they want
more highly flavored, spicy foods. A craving for fresh
rather than preserved food develops. Fluids remain
acceptable and many calories can be taken in sweet
milky drinks. Supplements such as vitamins and
minerals are probably not necessary if a balanced diet
is taken, with the possible exception of iron supplements for pre-menopausal women.

14.1

INTRODUCTION

Anorexia and weight loss are well known features of

life at high altitude, especially extreme altitudes. The

Energy balance at altitude 169

mechanism of this anorexia is not known. During the

first few days after a rapid ascent, anorexia may be
part of the symptomatology of AMS, but after this,
when all other symptoms of AMS are gone, anorexia
may remain. Recent studies have suggested that the
anorexia of AMS may be mediated by the hormone
leptin (Tschop et al. 1998) or by increased levels of
cholecystokinin (Bailey et al. 2000). This continuing
anorexia is not common below about 5000 m but is
almost universal above 6000 m and becomes worse at
even higher altitudes, though the severity varies considerably between individuals.
Weight loss is also common, though not inevitable,
even at extreme altitudes (see below) and is partly due
to the reduced energy intake consequent on the
anorexia, but the possibility that it might be due also
to other factors, such as malabsorption, is reviewed in
this chapter. This chapter also considers diet at
altitude and the evidence for the value of a high
carbohydrate diet.

14.2
14.2.1

ENERGY BALANCE AT ALTITUDE

Energy output

BASAL METABOLIC RATE (BMR)

Nair et al. (1971) found that after a week at 3300 m

the basal metabolic rate (BMR) was elevated by
about 12 per cent. Exposure to cold as well as
hypoxia (in a second group of subjects) made no difference to this effect compared with hypoxia alone.
By week 2, BMR was back to control values and was
below control by week 3. Cold exposure at this time
resulted in elevation of BMR to above sea level values
by week 5 and it remained elevated a week after
return to sea level. Butterfield et al. (1992) found
BMR to be elevated by 27 per cent on day 2 at Pikes
Peak (4300 m) in Colorado. The BMR then
decreased over the next few days to plateau at
+ 17 per cent compared with sea level by day 10.
After acclimatization, BMR measured at 5800 m
was found to be elevated by about 10 per cent in subjects who had been at altitude for 82-113 days (Gill
and Pugh 1964). It is likely that BMR rises again if
subjects climb to altitudes to which they are not
acclimatized and we have no data on BMR at altitudes above 6000 m when weight loss becomes even
more rapid, but its elevation might well be a factor.

BMR was found to be high at altitude in altitude

residents (Ladakhis and Sherpas) compared with
lowlanders and with predicted values (Gill and Pugh
1964, Nair et al 1971). This elevation of BMR
remained even when allowance was made for the fact
that these people generally have less fat in their body
composition. Picon-Reategui (1961) also reported
elevated BMR in Andean miners at 4540 m. The
mechanism for this rise in BMR is uncertain. Fecal
and urinary excretion of energy nitrogen and volatile
acids are not altered in the early days at altitude
(Butterfield et al. 1992). There is increase in sympathetic activity at this time (section 15.6) and the finding that this increase in metabolic rate can be
inhibited by a beta-blocker (Moore et al. 1987) suggests it is a likely factor. Increased thyroid activity
may also play a part, especially in the longer-term
elevation of BMR (section 15.7).
ENERGY EXPENDITURE DUE TO EXERCISE

Work in absolute terms requires the same oxygen

intake at altitude as at sea level until near-maximum
work rate is reached (Pugh et al. 1964, West et al.
1983c, Wolfel et al. 1991). At altitude the maximum
work rate is reduced (Chapter 11) and all activity
seems disproportionately fatiguing. At 8000 m, even
rolling over in a sleeping bag demands a great effort.
Thus, energy expenditure for normal activities of
daily living must be reduced at extreme altitude.
Another fact of life at extreme altitudes is that often
the only warm place is a sleeping bag and much of the
24 h of the day is spent lying down. The increased
work of breathing has a small opposite effect, as does
the increase in BMR, so that the daily energy expenditure is probably about the same as at sea level (see
below). At intermediate altitudes (2500-4500 m),
although maximum work rate is reduced, energy
expenditure on normal daily activities of short duration is probably not much altered. For longer-term
work such as hill climbing, much will depend upon
the degree of acclimatization and fitness. Pugh et al.
(1964) found V02 intake on climbers climbing at their
'preferred' rate to decline very little up to about
5000 m (Figure 11.1), whereas Butterfield et al. (1992)
found a 37 per cent reduction in energy expenditure
for exercise 'more strenuous than walking'. But the
overall requirement for energy to maintain body
weight increased from 13.22 MJ at sea level to
14.64 MJ a day at 4300 m due to the increase in BMR.

170 Nutrition and intestinal function

Until recently it has been impossible to measure

energy expenditure over long periods, but a doubly
labeled water technique has now been developed
which makes this possible. Water is labeled with both
deuterium and oxygen-18. The deuterium is eliminated as water while the oxygen is eliminated as both
water and carbon dioxide. Thus carbon dioxide production can be calculated from the different elimination rates (Schoeller and van Santen 1982, Coward
1991). Using this technique, Westerterp et al (1992)
found average daily energy expenditure in the Alps
(2500-4800 m) to be 14.7 MJ and on Mount Everest
(5300-8848 m) it was not significantly different at
13.6 MJ. Very similar daily results were obtained in
the 1992 British Winter Everest Expedition of
11.7-15.4 MJ (Travis et al. 1993). Pulfrey and Jones
(1996), using the same technique at altitudes of
5900-8046 m, found the very high mean values
of 19.4 MJ day"1 and a negative energy balance of
5.1 MJ day1. More recently Reynolds et al. (1999)
found an even higher mean value of 20.6 MJ day"1
above Base Camp with a dietary intake of only
10.5 MJ, giving a deficit of 10 MJ day-1!

14.2.2 Energy intake and caloric

balance
Up to about 4500 m, once acclimatized, people have
normal appetites and normal food intake
(Consolazio et al. 1968). Above 6000 m most
climbers experience anorexia. This tends to become
more pronounced the longer one stays at these altitudes. Climbers complain about the food available
and feel that the preserved nature of food increases
the anorexia and reduces their intake. There are few
data on actual calorie intake under these circumstances. Those that there are rely on diary cards and
estimates of portion size. On Cho Oyu in Nepal in
1952 food eaten at between 5250 and 6750 m was
only about 13.4 MJ a day compared with 17.6 MJ on
the march out, and on Everest in 1953, above
7250 m, the intake was only about 6.3 MJ (Pugh and
Band 1953). On the Silver Hut Expedition (1960-1),
in four climbers at 5800 m whose living conditions
were excellent and where a good variety and quantity
of food was available, a daily intake of 12.6-13.4 MJ
day1 was estimated (Pugh 1962a). Boyer and Blume
(1984) reported that on the American Medical
Expedition to Everest (AMREE) in 1981, over 3 days

four subjects had a mean intake of 9.34 MJ at 6300 m

compared with 12.5 MJ at sea level. Dinmore et al.
(1994) found intakes similar during the march in
(1500-2000 m) and above 5500 m (10.8 and
10.3 MJ). However, Westerterp et al. (1992) and
Travis etal. (1993) estimated intakes high on Everest
of 7.5 MJ and 8.6 MJ respectively, indicating the
expected reduction in intake above 6300 m.
Clearly, high on major mountains (above
6000 m), when actively climbing, it is not possible to
maintain caloric balance even when acclimatized.
Westerterp et al. (1994) on Mount Sajama (6542 m)
in Bolivia found an energy deficit of 3.5 MJ day1 in
10 subjects camped on the summit for 21 days. The
average weight loss was 4.9 kg (1.6 kg week"1),
74 per cent of it being due to loss of fat. In Everest
climbers studied by Westerterp et al. (1992) there
was a daily negative balance of 5.7 MJ. Clearly, more
studies using this new technique are needed to
answer the question of whether acclimatized subjects
can maintain energy balance at intermediate altitudes (4500-6000 m) when semi-sedentary.

143
WEIGHT LOSS ON ALTITUDE
EXPEDITIONS

14.3.1 Weight loss on the march out

Most climbing and trekking groups experience
weight loss in the initial 1-3 weeks of an expedition,
even when walking below 3000 m. This is probably
due to the change in lifestyle for most subjects from
an urban semi-sedentary existence to the more active
lifestyle of marching 16 km (10 miles) a day with
some considerable ascents and descents. In addition,
gastrointestinal infections are common.
Boyer and Blume (1984) found that 13 AMREE
members, during the march out to the Everest
region, lost an average of 2 kg (range 0-6 kg). Those
with the highest percentage of body fat to start with
lost most weight, the correlation being significant;
70 per cent of this weight loss was due to loss of fat.
Two subjects with less than 13 per cent of body fat
lost no weight. Dinmore et al. (1994) similarly found
an average loss of 1.3 kg during the first week of
trekking but only a further 0.5 kg in the next week.
Weight loss during this phase of an expedition or
trek can be considered as shedding unnecessary fat.

Weight loss on altitude expeditions 171

14.3.2

Weight loss at altitude

On first arrival at altitude, AMS may cause anorexia

and vomiting with resultant weight loss, though usually the duration is not long enough to do this. Also,
fluid may be retained and subjects with AMS often
gain weight (Hackett et al. 1982). Consolazio et al.
(1972) found a small gain in weight on the first day at
altitude followed by a loss of weight of about 1 kg
over the next 5 days at 4300 m. Recently leptin has
been discovered as a hormone which influences
appetite. In subjects taken to 4559 m by helicopter,
Tschop et al. (1998) found that the leptin levels in
those who complained of anorexia were higher than
those with no loss of appetite. Leptin is secreted in a
pulsatile manner with normal diurnal fluctuations so
it is necessary to measure it on a number of occasions
over some hours. This they did, as shown in Figure
14.1. This work suggests that leptin may be involved
in the mechanism of appetite loss at altitude but
needs confirmation.
After acclimatization, weight loss is usually seen
only above about 5000 m. Dinmore etal. (1994) found
an average loss of 3.9 kg during two weeks' climbing
above 5000 m; on the 1992 British Winter Everest
Expedition a mean weight loss of 5 kg was observed

Image Not Available

Figure 14.1 Serum leptin concentrations at 490 and 4559 m

(Capanna Margherita) in 18 subjects with and without loss of
appetite. The increase in leptin from low to high altitude (area
between curves) was significant for subjects with loss of appetite
(p = 0.008) but not for those with no appetite loss (p - 0.35). From
Tschop et a I. (1998) with permission.

Figure 14.2 Record of body weight of one subject during the

Silver Hut Expedition 1960-1. After the march out from
Kathmandu (K) and the initial period of preparation, he was in
residence at 5800 m (hatched areas) or at Base Camp at 4500 m.
Note the loss of weight at 5800 m but weight gain during two
breaks at 4500 m.

above 5400 m out of a total loss of 7.8 kg (Travis et al.

1993). Figure 14.2 shows the crucial effect of altitude
on body weight on one well acclimatized subject. The
combined effects of the march out and early residence
at the Silver Hut, at 5800 m, produced a weight loss
of 5.3 kg. Thereafter, during time spent at the Silver
Hut the subject lost weight steadily at a weekly rate of
just under 400 g, but, on two occasions, on descent to
altitudes of 4000-4500 m, he began to gain weight.
Most subjects in the Silver Hut lost between 0.5 and
1.5 kg a week (Pugh 1962a).
Rai et al. (1975) found no weight loss in their subjects living at 3500-4700 m, even though they were
working quite hard at road building and digging.
Indeed, on a high fat diet (232 g daily) they actually
gained an average of 1.4 kg during 3 weeks at 4700 m.
Butterfield et al. (1992) also found that it was possible
to attenuate weight loss at 4300 m by increasing
dietary intake in proportion to the increase in BMR.
However, at Advanced Base Camp (6300 m) in the
Western Cwm on Everest most subjects lost weight.
Boyer and Blume (1984) document this weight loss as
an average of 4 kg (range 0-8 kg) over a mean of
47 days in 13 subjects. Again, there was considerable
individual variation in the amount of weight lost
which correlated with initial percentage of body fat.
Boyer and Blume also found that Sherpas, who averaged only half as much body fat as the white climbers,
lost no weight during the time spent above Base Camp,
mostly at or above 6300 m (see also section 14.9).
Women seem to lose less weight than men do.
Hannon et al. (1976) found their female subjects lost

172 Nutrition and intestinal function

an average of only 1.8 per cent of body weight during

7 days at 4300 m whereas studies, previously
reported, of men at this altitude had found losses of
3.5 and 5.0 per cent. Collier et al (1997b) found
changes in body mass index at Everest Base Camp
(5340 m) over a median of 15 days: 22 men lost
0.11 kg nr2 day"1 compared with 0.02 kg nr2 day"1 in
eight women, a significant difference (p = 0.03). The
seven male climbers who climbed to between 7100
and 8848 m, using oxygen at extreme altitude, all lost
weight, averaging 0.15 kg m~2 day"1. The one female
climber who spent 4 nights above 8000 m without
supplementary oxygen lost no weight between leaving and arriving back at Base Camp!

143*3 Weight loss in chamber

experiments
It could be argued that some of the weight loss on
expeditions is due to cold, limited food supplies, and
the increased energy expenditure of climbing. This
may often be the case, although not so in a number of
the studies quoted above. Chamber studies avoid this
potential criticism; most are of too short a duration
to be relevant, but the two Operation Everest studies
of 40 days' duration showed that, despite good environmental conditions of temperature, humidity and
diet ad lib., subjects lost weight (Rose et al 1988). In
Operation Everest II the six subjects lost an average
of 7.4 kg during the 38 days of observations as they
ascended the simulated height of the summit of
Everest. Energy intake fell by 43 per cent and, interestingly, the subjects chose a diet that resulted in a
reduction of carbohydrate from 62 per cent to
53 per cent of the total diet. The authors considered
that the weight loss could not be accounted for
totally by the reduction in intake and considered that
malabsorption or increase in energy expenditure due
to increased BMR must be invoked (section 14.2.1).
The exercise taken in this chamber study would
probably be less than on a climbing expedition.

14*4
LOSS

BODY COMPOSITION AND WEIGHT

Assuming much of the weight loss is due to negative

energy balance, a simplistic view would be that the
body would use up fat stores first and then start using

protein from the lean body mass, principally the

muscles. However, even with a most carefully controlled diet aimed at fat reduction, it is never possible
to lose fat exclusively and retain all the lean body
mass (Garrow 1987). The best that can be achieved is
that, of the weight lost, 75 per cent is fat and
25 per cent lean body tissue. This compares with the
situation during a complete fast when fat and lean
body tissues are lost in roughly equal proportions
(Forbes and Drenick 1979).
Boyer and Blume (1984) used skinfold measurements to estimate body fat. There are uncertainties
about the absolute results of this method, but relative
changes probably can be reliable. They found that, of
the average 2 kg loss during the march out to Base
Camp, 70 per cent was due to loss of fat, which is a
figure close to the most efficient muscle sparing regimen available. However, above 5400 m, mainly at or
above 6300 m, of the 4 kg average weight loss only
27 per cent was due to loss of fat and 73 per cent due
to loss of lean body tissue, despite the fact that subjects still had at least 10 per cent of their body weight
as fat. This percentage loss of muscle, greater than
that seen in starvation, suggests that at this altitude
hypoxia may be interfering with protein metabolism
(section 14.5).
In the Operation Everest II study (Rose et al. 1988)
there was loss of 2.5 kg of fat (1.6 per cent body
weight) and 4.9 kg of lean body tissue. Computerized
tomographic examination of the thigh showed a
17 per cent loss of muscle and a 34 per cent loss of
subcutaneous fat. Although loss of muscle mass must
be a disadvantage, one beneficial effect is to increase
the density of muscle capillaries. This is because the
loss of muscle mass is achieved by reducing fiber
diameter rather than number, with the number of
capillaries per fiber remaining constant. Thus the
intercapillary distance decreases with an improvement in oxygenation of the muscles (Chapter 10).
Evidence in support of this speculation is found in
the work of Oelz et al. (1986), who studied muscle
biopsies from six elite climbers at sea level some
months after return from altitude. It was found that
their muscle fibers were smaller and the capillary
density greater than controls. Another explanation
for the loss of muscle mass is that with decreased
overall activity at altitude there is some disuse
atrophy which would similarly reduce muscle fiber
diameter. These two explanations are not mutually
exclusive. Results of muscle biopsy studies during

Intestinal absorption and hypoxia 173

Operation Everest II (MacDougall et al. 1991)

showed similar histological changes in muscle fiber
size (Chapter 10 contains a fuller discussion of
changes in muscle histology).

14.5
INTESTINAL ABSORPTION AND
HYPOXIA
In view of the continued weight loss at altitudes
above 5000 m with, in some cases, adequate intake
and reduced energy output, the possibility of malabsorption and malutilization of food must be considered. Pugh (1962a) reported that members of the
Silver Hut Expedition noted that stools tended to be
greasy and bulky, suggesting possible steatorrhea due
to malabsorption of fat.
As mentioned in section 14.3, weight loss is not a
feature of living at altitudes below about 5000 m, and
the fact that most altitude research is conducted
below this level may explain why so little work has
been carried out on the topic of intestinal absorption. Other reasons for the neglect of this field may
be that the methods involved are either too sophisticated for easy use in the field (e.g. absorption of
radioactive materials), or are unattractive to investigators (e.g. fecal collection, liquidization and aliquot
sampling, etc.). Finally, few altitude physiologists
have a background in gastroenterology.
14*5.1 Carbohydrate absorption and
hypoxia
Milledge (1972) studied patients who were hypoxic
either because of congenital heart disease or chronic
obstructive lung disease. Xylose absorption
decreased with decreasing arterial oxygen saturation
(Figure 14.3).
On relieving the hypoxia by surgery in the cardiac
cases, or by 13 h of supplementary oxygen breathing
in the respiratory cases, there was improvement in
xylose absorption in all patients. The xylose absorption test has a rather uncertain lower normal limit,
especially in a population in which intestinal parasitic infection is common (the study was carried out
in South India). However, the results suggest that,
below an arterial saturation of about 70 per cent,
absorption was impaired (Figure 14.3); improvement on relief of hypoxia supports this view.

Figure 14.3 Xylose absorption in patients hypoxic because of

either congenital cyanotic heart disease (O), or chronic respiratory
disease (9), plotted against their arterial oxygen saturation.

Pritchard and Lane (1974) did not find malabsorption in 26 patients with chronic obstructive lung
disease. However, the lowest arterial P02 was
48 mm Hg, equivalent to about 78 per cent saturation. Chesner et al. (1987) found no malabsorption
of xylose in 11 subjects up to 4846 m. However,
60-min plasma xylose concentrations were reduced
in subjects who ascended to 5600 m, confirming that
absorption is not affected until hypoxia is severe.
Boyer and Blume (1984), who studied subjects at
6300 m, found xylose absorption decreased by
24 per cent in six out of seven subjects, compared
with sea level controls.
However, absorption measured by xylose has the
drawback that the result is influenced by factors such
as gastric emptying time, absorption area, intestinal
transit and renal function. Dinmore etal. (1994) used
a double carbohydrate test; the two nonmetabolized
carbohydrates used undergo different forms of mediated absorption but are otherwise subject to the same
external influences which cancel out when results are
expressed as a ratio (Menzies 1984). D-xylose is
absorbed by passive mediated transport, whereas 3-0methyl-D-glucose is absorbed by active mediated,
sodium-dependent transport. Dinmore et al. found
that at 6300 m there was 34 per cent decrease in Dxylose (Figure 14.4) and a 15 per cent decrease in 3o-methyl-D-glucose absorption. The ratio was
consistently decreased at altitude and in a subsequent
study the 60-min serum xylose/3-o-methyl-D-glucose
ratio was 17 per cent lower at 5400 m than at sea level
(Travis et al. 1993). These more sophisticated studies

174 Nutrition and intestinal function

3 weeks at 5000 m. Westerterp et al. (1994) on

Mount Sajama (6542 m) found that gross energy
digestibility decreased to 85 per cent, indicating
some malabsorption, though most of the weight loss
was attributable to low food intake.
14.5.4

Summary: malabsorption at

altitude

There is no evidence of malabsorption up to an altitude of about 5000 m and this has been confirmed by
measurements of fecal energy excretion which have
shown that 96 per cent of energy intake is assimilated
(Kayser et al. 1992). Above 5000 m, however, there
may be malabsorption of carbohydrate, fat and protein. The mechanism of this hypoxic malabsorption
is unknown. It might be due to bowel wall hypoxia,
or the fat malabsorption could be due to pancreatic
insufficiency and the xylose malabsorption secondary to fat malabsorption.
14.6

INTESTINAL PERMEABILITY

Figure 14.4 o-xylose absorption tested in a group of climbers at

sea level (UK), at altitudes indicated in Nepal and after return to
UK (with mean and S.D. values at each location). (Data from
Dinmore et al. 1994.)

therefore support the hypothesis that at these high

altitudes carbohydrate absorption is impaired.

14.5.2

Fat absorption and hypoxia

Rai et al. (1975) found no malabsorption for fat at

4700 m; neither did Chesner et al. (1987) at 3100 m
and 4800 m. Imray et al. (1992), using the [14C]-triolein breath test, found no malabsorption of fat at
5500 m on Aconcagua in Argentina, and Butterfield
et al. (1992) found no increase in fecal excretion of
volatile fatty acids at 4300 m. However, Boyer and
Blume (1984) found fat absorption decreased by
49 per cent at 6300 m compared with sea level results
in three acclimatized subjects.

14.53

Protein absorption and hypoxia

Kayser et al. (1992) measured protein absorption

using urinary and fecal nitrogen-15 excretion after
ingestion of nitrogen-15 labeled soya protein. They
found no reduction in absorption in subjects after

Pappenheimer (1988) showed that the space between

adjacent epithelial cells in the small intestine (zona
occludens) became less with hypoxia. This may be by
contraction of the actin-myosin cytoskeletal system
(myoepithelial cells) which control the caliber of
these pores. This would reduce sodium-coupled
transport of material across the luminal cell wall.
Intestinal permeability is the facility with which
molecules pass through the intestinal epithelium by
passive, nonmediated transport. It can be measured
by the ratio of urinary lactulose and L-rhamnose after
ingestion of these test carbohydrates (Travis and
Menzies 1992). Lactulose is thought to permeate
through paracellular pores of low frequency and Lrhamnose through transcellular pores at a much
higher rate (Menzies 1984). Permeability increases if
the integrity of the intestinal mucosa is compromised
by, for instance, mucosal damage. Dinmore et al.
(1994) measured intestinal permeability in this way
in 11 climbers. After arrival in Nepal there was an
increase in permeability due possibly to 'tropical
enteropathy' because of changes in gut flora. This is
normally a transient phenomenon in travelers to the
tropics. When the climbers ascended to altitude,
studies at 5730 m showed that the ratio returned to
sea level values (Figure 14.5).

Diet for high altitude 175

Figure 14.5 Intestinal permeability (lactoseA-rhamnose ratio) in a

group of climbers tested at sea level (UK), at altitudes indicated in
Nepal and after return to the UK (with mean and S.D. values at
each location). Results show an increase in permeability after
arrival in Nepal, possibly due to a change in gut flora, but a return

Pikes Peak (4300 m), below the crucial height at

which continued weight loss is observed.
Rennie et al. (1983) studied the effect of acute
hypoxia in a chamber (equivalent altitude 4550 m)
on leucine metabolism in forearm muscles. They
found that acute hypoxia resulted in a net loss of
amino acids from the muscles, probably due to a fall
in muscle protein synthesis. If this finding can be
extrapolated to the situation of chronic hypoxia at
altitudes of above 5000-6000 m (where hypoxia in
acclimatized subjects would be similar to that in the
above study), then it provides a further contributing
factor to the loss of muscle mass described above. It
has been suggested that protein or branched-chain
amino acid (BCAA) supplementation might be helpful in reducing the muscle loss. Bigard and colleagues
(1996b) gave one group of skiers BCAA supplementation while participating in six sessions of ski mountaineering at altitudes of 2500-4100 m. They found
that they did no better than a control group given
98 per cent carbohydrate supplement with respect to
changes in body composition or performance of isometric contraction. However, body weight loss was
possibly less in the BCAA group. In another study
(Bigard et al. 1996a) they found that adding protein
to the diet of growing rats did not affect the depression of muscle growth caused by altitude.

to sea level values at 5730 m. (Data from Dinmore et al. 1994.)

However, the transcellular permeation of the

monosaccharide L-rhamnose showed a 45 per cent
decrease at 5730 m, which is a change unique to high
altitude. These findings suggest that at these high
altitudes the 'porosity' of the gut is unchanged but
that changes maybe occurring in the epithelial membranes, perhaps through a change in membrane fluidity (Travis and Menzies 1992).

14.7

PROTEIN METABOLISM AT ALTITUDE

The obvious muscle wasting seen especially in

climbers returning from extreme altitude prompts
the question of whether hypoxia affects protein
metabolism directly. There are very few data on this
topic in humans.
Consolazio etal. (1968) studied protein balance at
altitude and found no difference between subjects
there and at sea level, but the altitude station was

14.8

DIET FOR HIGH ALTITUDE

Views on diets (not only at altitude) are strongly

held, often the strength of opinion being inversely
related to the strength of scientific evidence.

14.8.1

High carbohydrate diet

There is a preference amongst climbers for a high

carbohydrate, low fat diet at altitude and there are
good physiological reasons for this. Figure 14.6
shows the basis for advising a high carbohydrate diet,
which moves the respiratory quotient (RQ) from 0.7,
if one uses fat exclusively for energy, to 1.0 when
carbohydrate (or protein) is used.
The result of such a change of RQ is that for any
given fAc02 the PA02 is increased. In the case illustrated in Figure 14.6, the subject is considered to be
at 5800 m in the Himalayas or Andes when the barometric pressure is half that at sea level and the PI02 is

176 Nutrition and intestinal function

If you do succeed in getting outside a richly concentrated food like pemmican a great effort of will is
required to keep it down - absolute quiescence in a
prone position and a little sugar are useful aids.
Eating a large mug of pemmican soup at 27 200 feet
as Peter Lloyd and I did in '38 is, I think, an unparalleled feat and shows what can be done by dogged
greed (Tilman 1975).

Figure 14.6 Oxygen-carbon dioxide diagram showing the effect

of the respiratory quotient (RQ) on alveolar ?02 at a given PAC02. By

There are good physiological reasons for a low fat

diet at altitude: the effect of fat as an energy source on
the RQ (as discussed above) and the possible effect of
fat malabsorption on the absorption of sugars and
amino acids. This fat intolerance is unfortunate
because fat provides more calories weight for weight
than carbohydrate or proteins.

changing from an RQ of 0.7 (the RQ when utilizing fat) to 1.0 (the

RQ when using carbohydrate) the PA02 is increased from 37.2 to

14.83

47.0 mm Hg.

70 mm Hg. PACC,2 is assumed to be 23 mm Hg. With

an RQ of 0.7 the PA02 would be 37.2 mmHg,
whereas with an RQ of 1.0 it would be 47 mm Hg;
this is a very important gain in arterial oxygen saturation. This represents the extreme case of a switch
from pure fat to pure carbohydrate utilization, but
even a partial switch in this direction would be helpful to the climber at extreme altitudes.
Consolazio et al. (1969) compared a normal with a
high carbohydrate diet in two groups of subjects at
4300 m. The performance of the group on a high
carbohydrate diet was superior in that they had a
greater endurance for heavy work, though Vo2maxwas
not significantly better. Also, the symptoms of AMS
were less in the high carbohydrate group.
Another reason for recommending a high carbohydrate diet is that the body becomes more dependent upon blood glucose as a fuel both at rest and on
exercise after acclimatization (Brooks et al. 1991,
Roberts et al 1996). However, Reynolds et al. (1998)
in a study on Everest found that subjects did not shift
their food selections from high fat towards high
carbohydrate items as they ascended from Base
Camp to camps higher up the mountain.

IRON
Since the red cell mass is increased at altitude it has
been suggested that extra iron should be taken.
Unless there is pre-existing iron deficiency the iron
stores of the body and the iron content of a normal
diet will be adequate. However, in premenopausal
women there may be a degree of deficient iron stores
and the addition of iron maybe indicated (Richalet et
al. 1994). A rapid response to hypoxia is an increase
in intestinal iron absorption from the gut before any
change in plasma iron turnover, at least in rats and
mice (Hathorn 1971, Raja et al. 1986). Thus the iron
stores of the body are replenished even before they
begin to be depleted.
VITAMINS
It is common for expedition and trekking parties to
take added vitamins, but although such dietary supplements probably do no harm, there is no evidence
that they are needed provided that a normal, balanced diet is taken.

14.8.4
14.8.2

Other dietary constituents

Fresh food, flavor, variety

Low fat diet

Most climbers find fatty foods become distasteful at

altitude, in contrast to the preference shown by Arctic
and Antarctic travelers. Tilman, who was experienced
in both Arctic and mountain travel, writes:

The appetite becomes jaded at high altitude and the

most common complaints on expeditions are about
the drab sameness of the flavor of preserved foods.
More experienced climbers tend to adopt a policy of
eating local fresh foods, supplemented by the

Nutrition and metabolism in high altitude natives 177

minimum of imported preserved foods. The sense of

taste seems to be dulled at altitude, and western food
tastes insipid. The addition of strong flavors such as
curries and herbs is increasingly appreciated. There is
great individual variation in likes and dislikes, even
more than at sea level. The wise quartermaster of an
expedition will attempt to meet this by providing as
wide a variety of foods and flavors as possible.
However, the task is unenviable since, whatever the
quartermaster provides, fellow expedition members
will yearn for what is unavailable.
14.9
NUTRITION AND METABOLISM IN
HIGH ALTITUDE NATIVES
Little work has been done on nutrition in peoples
native to high altitude. There is the impression that

Sherpas do better than lowland climbers with respect

to weight loss, and Boyer and Blume (1984), as mentioned in section 14.3.2, documented this. There are
caretakers who live at the Aucanquilcha mine in
Chile (5950 m) for 1-2 years. Presumably they do
not lose weight in the relentless way we did in the
Silver Hut (5800 m), though it must be added that
only a subset of miners is able to stay at this altitude
indefinitely (West 1998, p. 227).
Hochachka etal. (1996) studied the metabolism of
Sherpas under normoxic and hypoxic conditions.
They found that, compared to lowlanders, the
Sherpas made greater use of carbohydrate substrates
for cardiac function and less use of free fatty acids.
This metabolic organization is advantageous in
hypoxic conditions because the ATP yield per molecule of oxygen is 25-60 per cent greater with glucose
than with free fatty acids.

15
Endocrine and renal systems at altitude
15.1
15.2
15.3
15.4
15.5
15.6

Introduction
Antidiuretic hormone
Renin-angiotensin-aldosterone system
Altitude and atrial natriuretic peptide
Corticosteroids and altitude
Adrenosympathetic system

179
179
180
183
184
185

SUMMARY

The chronic hypoxia of altitude has an effect on

many endocrine systems. Among those most studied
are hormones that affect the salt and water balance of
the body and are involved in cardiovascular
function. Exercise affects many hormonal systems
and is an important activity at altitude; the effect of
altitude and exercise therefore needs to be considered. The possible role of certain hormones in the
mechanism of acute mountain sickness (AMS) has to
be addressed by comparing levels in subjects with
and without AMS.
Levels of antidiuretic hormone (ADH) are not
affected by altitude, exercise or AMS except in cases
with severe nausea when levels are elevated. After full
acclimatization and at more extreme altitudes there
is high osmolality with inappropriately low levels of
ADH.
The renin-angiotensin-aldosterone system is
activated by exercise and, in the case of the long
continued exercise involved in mountaineering, can
produce sodium and some water retention.
Altitude in the absence of exercise results in lower
levels of aldosterone, but exercise involved with
ascent to altitude results in raised levels of aldosterone.

15.7

Thyroid function and the altitude

environment
15.8 Control of blood glucose at altitude
15.9 Endothelin
15.10 Altitude and other hormones
15.11 Renal function at altitude

186
187
188
189
190

On first arrival at altitude, corticosteroids are

elevated by ACTH then decline to baseline levels over
5-7 days. Even in subjects who had spent some weeks
above 6000 m, corticosteroid levels were normal, but
one report of subjects who spent months at this
altitude did show high levels.
The adrenosympathetic system is stimulated
during the first few days at altitude with high levels of
urinary catecholamines. These decline with acclimatization in line with the changes in resting heart rate.
Thyroid function is enhanced in humans at
altitude, unlike in animals in which it is depressed by
hypoxia. Because of this and the increased sympathetic activity, basal metabolic rate (BMR) is
increased on going to altitude and remains elevated
after acclimatization.
Insulin and glucose levels tend to be lower at
altitude, indicating increased insulin sensitivity.
Plasma endothelin levels are raised by hypoxia in
line with the raised pulmonary artery pressure and
are high in high altitude pulmonary edema (HAPE)
patients and subjects susceptible to HAPE.
Glucagon, growth hormone, bradykinin and the
sex hormones are little affected by hypoxia except
that the exercise response to growth hormone is
enhanced and sex hormones tend to be decreased.
Renal function is remarkably little affected by
altitude. At extreme altitude, above 6500 m, renal

Antidiuretic hormone 179

compensation for further respiratory alkalosis seems

to be incomplete. There is an increase in microproteinuria, especially on first going to altitude,
which is greater in subjects with AMS.

that their subjects developed peripheral (exercise)

edema associated with sodium retention (section
15.3.3).

15.2.2
15.1

INTRODUCTION

Endocrinology comprises many systems controlling

a great variety of bodily functions and the effect of
altitude has been studied on only a fraction of these.
The areas studied reflect the interests of scientists
going to altitude. Thus hormones that play a part in
fluid and electrolyte balance have been widely
studied because of their possible relevance to AMS
and its complications, as have thyroid hormones
because of their effect on metabolic rate. Another
factor in the selection of systems for study has, of
course, been the availability and ease of relevant
assays. This chapter surveys the principal systems
studied to date but clearly there are great areas of
endocrinology in which the effects of acute and
chronic hypoxia have yet to be explored.
The study of endocrinology at altitude is perfectly
feasible, but attention to details of sampling, such as
time of day, subject's posture, diet and exercise is
required, as it is in studies at sea level. Practical
aspects of collection and storage of samples are
discussed in Chapter 32.

Forsling and Milledge (1977) found that breathing

10-10.5 per cent oxygen for 4 h had no effect on
ADH levels in samples taken at intervals of from
3 min to 4 h of hypoxia. In a chamber experiment,
where subjects were taken to an equivalent altitude of
4000 m for 14 h, there was no significant change in
ADH plasma concentration until subjects began to
feel nauseated, when levels rose markedly (Forsling
and Milledge 1980). Claybaugh et al (1982) took
subjects to various equivalent altitudes in a chamber
and found an initial increase of urinary ADH at
8-12 h of hypoxia with subsequent return to sea level
values. In two subjects with AMS there was a rise in
urinary excretion of ADH at 2-4 h of hypoxia. De
Angelis et al. (1996) studied 26 young pilots in a
chamber at an altitude of 5000 m equivalent for 3 h.
They found a significant increase in ADH as a result
of this quite severe hypoxic stress. It would seem,
therefore, that acute hypoxia alone has very little
effect but nausea due to AMS is associated with a rise
in ADH, analogous to that seen in motion sickness
(Eversman et al. 1978).

15.2.3
15.2

ANTIDIURETIC HORMONE

There is considerable evidence that ascent to altitude

is associated with changes in body fluid compartments both in those with AMS and in asymptomatic
subjects. Not surprisingly, therefore, investigators
have studied the role of ADH in both the normal
(healthy) response to hypoxia and AMS. Reports on
the effect of hypoxia on ADH have given conflicting
results.
15.2.1

Exercise and ADH

Williams et al. (1979) studied exercise in the absence

of hypoxia. They studied the effect of daylong hill
walking over 7 consecutive days and found no
alteration in ADH concentration, despite the fact

Acute hypoxia and ADH

Chronic hypoxia and ADH

Studies conducted in the field include one by Singh et

al. (1974), who measured a number of hormones in a
group of subjects who had a history of HAPE. In
those who remained free of symptoms on going to
altitude, there was no change in ADH concentration.
In subjects who became sick there was a tendency to
higher levels but this was mainly seen after a few days
at altitude and was not statistically significant.
Harber et al. (1981) found no significant change in
urinary ADH concentration on going to altitudes up
to 5400 m; nor was there any relationship with AMS.
Even in a fatal case of high altitude cerebral edema
there was no significant rise in ADH. Cosby et al.
(1988) found higher levels of ADH in five skiers with
HAPE compared with controls at the same altitude,
but the difference did not reach statistical significance. Ramirez et al. (1992) found no change in
ADH with altitude.

180 Endocrine and renal systems at altitude

Hackett et al. (1978) found normal levels in

trekkers at 4300 m, including those with and without
symptoms of AMS; the only exceptions were higher
concentrations in two cases of RAPE.
The conclusion from this work would seem to be
that hypoxia per se has no significant effect on ADH
concentration. High values may be associated with
AMS but not all cases have high values (Claybaugh et
al. 1982). Where high concentrations are found they
maybe an effect of AMS rather than its cause.

15.2.4 Inappropriate ADH secretion at

altitude
Blume et al. (1984) presented evidence of inappropriately low excretion of ADH at altitude. They
studied 13 subjects after some weeks at 5400 m and
6300 m on Everest during the American Medical
Research Expedition to Everest (AMREE) in 1981 and
found ADH concentration unchanged from sea level
despite a significant increase in plasma osmolality
with increasing altitude. At 6300 m the serum
osmolality was 302 mosm kg"1 compared with
290 mOsm kg"1 at sea level (normal value 280-295
mOsm kg"1). An overnight dehydration test at sea
level which might produce this degree of hyperosmolality would result in ADH concentrations of
about 7 |lU mL~', whereas subjects on Everest had a
mean value of only 0.9 (J.U ml/4; 12-h urinary ADH
showed the same lack of response. Sodium, potassium, calcium and phosphate concentrations were all
modestly increased compared with sea level values. A
study by Ramirez et al. (1992) confirmed these
observations. They increased osmolality by intravenous sodium, loading a group of subjects at sea
level and at altitude (3000 m). At sea level there was
the expected rise in ADH but at altitude there was no
significant rise. Thus, at altitude, there seems to be a
failure of the osmoregulatory mechanism. This is the
converse of the clinical syndrome of inappropriate
ADH secretion often associated with small cell
carcinoma of the lung (Bayliss 1987). In such cases
serum sodium concentration and osmolality are low
but ADH secretion is inappropriately high. A more
recent study (Ramirez et al. 1998) found evidence of
reduced sensitivity of the kidney to ADH in acclimatized individuals and that infusion of exogenous
ADH caused an increase of urinary arginine vasopressin (AVP) sensitive water channel (aquaporin-2).

153 RENIN-ANGIOTENSINALDOSTERONE SYSTEM

This system is depicted in Figure 15.1. Renin is
released in response to a number of stimuli, including posture, exercise and, possibly, hypoxia. The
mechanism common to these stimuli is sympathetic
activation, and both circulating catecholamine and
direct sympathetic nervous stimulation result in
release of renin from the juxtaglomerular apparatus
of the kidney.
Renin has no biological activity but acts on its
circulating substrate (angiotensinogen), cleaving it
to produce the octapeptide angiotensin I, which is
also devoid of activity. Angiotensin converting
enzyme (ACE), found on the luminal surface of
endothelial cells, converts angiotensin I to angiotensin II by cleaving the final two amino acids. The
principal site of conversion is in the rich capillary
network of the lung where nearly 90 per cent of
angiotensin I is converted to angiotensin II in a single
passage. Angiotensin II is a powerful vasopressor and
also acts on the cells of the adrenal cortex via a
receptor mechanism to release aldosterone. Aldosterone acts on the renal tubules, promoting the
reabsorption of sodium. In this way the system is
important in the salt and water economy of the body,
which is why it has been quite intensively studied at
altitude.

Figure 15.1 Renin-angiotensin-aldosterone system. Renin and

angiotensin converting enzyme (ACE) act as enzymes hydrolyzing
angiotensinogen and angiotensin I to angiotensin II. The latter
stimulates release of aldosterone from adrenocortical cells by a
receptor mechanism.

153.1

Aldosterone and altitude

Indirect evidence of the effect of altitude on aldosterone activity was first provided by Williams
(1961), who brought back samples of saliva from the

Renin-angiotensin-aldosterone system 181

Karakoram. The ratio of sodium to potassium in

these samples indicated suppression of aldosterone
at altitude. This has been confirmed by direct
measurements of either plasma aldosterone concentration or urinary metabolites (Tuffley et al. 1970,
Hogan et al. 1973, Frayser et al. 1975, Pines et al.
1977, Sutton et al. 1977, Keynes et al. 1982, Ramirez
etal. 1992,Antezanaefa/. 1995, Zaccaria etal 1998).
In one study the secretion rate was shown to be
reduced (Slater et al. 1969). Milledge et al. (1983a)
studied the time course of the effect of altitude over a
6-week stay at or above 4500 m. After initial suppression, aldosterone concentration rose to control
values after 12-20 days. All these studies were made
on resting subjects. In subjects who had been above
6000 m for more than 10 weeks and had expanded
fluid compartments (blood volume 85 per cent
above normal) the aldosterone concentration was
twice normal (Anand et al. 1993). These subjects
were probably in incipient subacute mountain
sickness (Chapter 21).

153.2

Renin activity and altitude

The effect of altitude on plasma renin activity (PRA)

has been studied by a number of groups with
conflicting results. Some have found a rise (Slater et
al. 1969, Tuffley et al. 1970, Frayser et al. 1975) and
others a fall (Hogan et al. 1973, Maher et al. 1975a,
Keynes et al. 1982, Antezana et al. 1995, Zaccaria et
al. 1998) and one group no change (Sutton et al.
1977). However, most studies have shown a reduced
response of aldosterone to renin. This is obvious
where PRA has increased and aldosterone has
decreased but even where both have declined, the
reduction in aldosterone has usually been greater.
It is not clear why these different studies produced different results. One possibility is that subjects, though sampled at rest, may have been more
active in some studies, resulting in a rise in PRA.
However, this is unlikely in view of the fact that one
study showing a rise in PRA was conducted in a
chamber (Tuffley et al. 1970) and in another, samples were taken before getting up in the morning
after subjects had been flown to altitude in a helicopter (Slater et al. 1969). The main stimulus to
renin release is thought to be sympathetic drive and
this certainly occurs with exercise but is probably
also induced by altitude hypoxia alone if sufficiently

severe (section 15.4), although with great individual

variation.

1533
Exercise and the
renin-aldosterone system
Since exercise frequently accompanies ascent to
altitude, the effect of exercise needs to be considered
in relation to the effect of altitude. Exercise stimulates renin release via activation of the adrenosympathetic system. The effect can be blocked by
beta-blockers (Bonelli et al. 1977, Bouissou et al.
1989). After intense short-term exercise (3 x 300 m
sprints in 10 min) PRA, angiotensin II and aldosterone concentration were elevated at 30 min but
measurable elevation was still present up to 6 h later
(Kosunen and Pakarinen 1976). The rise in PRA is
also proportional to the intensity of the work, both at
sea level and at altitude (Maher et al. 1975a).
Mountaineers are more concerned with daylong
exercise, often continuing for a number of days.
Williams et al. (1979) showed that this form of
exercise resulted in marked sodium retention after
7 days and suggested that this was due to activation
of the renin-aldosterone system. There was a mean
cumulative retention of 358 mmol of sodium with a
modest retention of 650 mL of water. Since plasma
sodium concentration did not change significantly it
was argued that the extracellular space must have
been expanded by 2.68 L(of which 0.68 L was in the
plasma volume), mainly at the expense of the intracellular volume. These calculated changes are shown
in Figure 15.2. This increase in extracellular fluid
(ECF) is the probable cause of the dependent edema
frequently found after exercise of this sort.
The same group (Milledge et al. 1982) studied the
effect of 5 consecutive days' hill walking on the
renin-aldosterone system and on sodium and water
balance, and confirmed the suggestion, from the
previous study, that the sodium retention was due to
activation of the renin-aldosterone system. There
was elevation of PRA and aldosterone at the conclusion of each day's exercise. This was maximal on
day 2 or 3 and less marked on days 4 and 5, perhaps
reflecting a training effect. Values were back to
control on day 2 after stopping exercise. The effect of
exercise and altitude was studied by repeating the
same protocol but on the first exercise day subjects
climbed to 3100 m and stayed there for 5 days,

182 Endocrine and renal systems at altitude

Figure 15.2 Calculated changes in body fluid compartments with

exercise at sea level. (From Williams et al. 1979.)

exercising for 8 h each day. The results were very

similar to sea level results in terms of changes in fluid
and sodium balance and hematocrit. Renin and
aldosterone also increased, but the aldosterone
response to the renin rise was blunted (see section
15.3.5; Milledge etal. 1983b).

153.4

level the same phenomenon is seen. This is shown in

Figure 15.3, which shows data from three studies, at
sea level, at 3100 m and on Mount Everest. This
blunting has been confirmed by Shigeoka et al.
(1985), who found the response completely abolished by hypoxia, by Lawrence et al. (1990), and, in
acute hypoxia, by De Angelis et al. (1996). Antezana
et al. (1995) also found the response in lowlanders to
be blunted in La Paz (3600m). Andean highlanders
with polycythemia showed a reduced response but
highlanders without polycythemia had a normal
response at this altitude.
The cause of this blunting is not entirely clear. It
had been suggested that ACE activity was reduced by
hypoxia, but most workers have found this not to be
the case (Milledge and Catley 1987, Bouissou et al.
1988). However, Vonmoos et al. (1990) have found
that, although angiotensin I levels were unchanged
with acute hypoxia, levels of angiotensin II were
reduced. The next stage in the promotion of aldosterone release is adrenal stimulation by angiotensin
II. Colice and Ramirez (1986) studied the effect of
angiotensin II infusion on aldosterone release and
found that hypoxia had no effect, suggesting that it
did not result in an increase of inhibitors of this part
of the system. However, Raff and Kohandarvish
(1990) found evidence that adrenocortical cells in
vitro were less responsive to angiotensin II under
hypoxic conditions. More recently Raff et al. (1996)

Control of aldosterone release

The control of aldosterone release via renin and

angiotensin has been mentioned above and is shown
in Figure 15.1, but ACTH and the sodium status of
the subject also control aldosterone concentration.
Salt depletion increases aldosterone release whereas
salt loading inhibits it. Anderson et al. (1986) have
shown that atrial natriuretic peptide (ANP) infusion
inhibits the response of aldosterone to angiotensin II.

153.5 Effect of altitude on the

aldosterone response to renin
Milledge and Catley (1982) showed that, if after 1 h
of exercise the inspired oxygen was reduced, renin
activity increased while aldosterone levels decreased,
indicating that the aldosterone response to renin
became blunted. In the chronic situation of hill
walking or climbing at altitude compared with sea

Figure 15.3 Plasma aldosterone concentration (PAC) response to

plasma renin activity (PRA)from a sea level (SL) study and from
two separate altitude studies. (From Milledge et al. 1983b.)

Altitude and atrial natriuretic peptide 183

have shown that chronic hypoxia in rats (10 per cent

oxygen for 3 days) results in a decrease in expression
of the steroidogenic enzyme P-450cllAS in adrenocortical cells. This enzyme is unique to the aldosterone pathway. However, with less severe hypoxia,
12 per cent oxygen for 3 days, there was no effect.
Aldosterone secretion is stimulated by ACTH as
well as by angiotensin II. Ramirez et al. (1988) found
this effect to be reduced in subjects at altitude
whereas the ACTH-induced secretion of cortisol was
unaffected. ANP has been found to inhibit aldosterone release (Elliott and Goodfriend 1986). It is
therefore possible that the rise in ANP on going to
altitude (section 15.4.4) may be a factor in blunting
this response at rest (Lawrence et al. 1990) and on
exercise (Lawrence and Shenker 1991).

15.4 ALTITUDE AND ATRIAL

NATRIURETIC PEPTIDE

15.4*1

ANP release and actions

ANP is secreted by the atria of the heart in response

to stretching. Atrial stretch is usually caused by an
increase in atrial pressure. However, in the case of
cardiac tamponade the pressure is high but the atrial
wall is not stretched. As the tamponade is relieved the
pressure falls and the atrium dilates. It has been
found that relief of tamponade results in a rise in
ANP plasma levels, indicating that stretch rather
than pressure is the stimulus for ANP synthesis and
release (Au et al. 1990).
Amongst its actions, ANP has the effect of
increasing sodium excretion by the kidneys and thus
of promoting a natriuresis and diuresis (Morice et
al. 1988). This provides a homeostatic mechanism
for salt and water. If the plasma volume is increased,
the raised atrial pressure results in atrial stretch and
secretion of ANP, diuresis follows and vascular
pressures and volume return to normal. This system
is further considered in relation to the regulation of
plasma volume in Chapter 8 (section 8.2.2). ANP
possibly also has a role as a vasodilator, countering
the pressor effect of hypoxia on the pulmonary
artery. It has been shown to have this effect in a
dose-dependent manner in the isolated rat lung
(Stewart et al. 1991) and in the pig (Adnot et al.
1988). Liu et al (1989) infused ANP (20 mg min-1

for 10 min) into four patients with HAPE and

showed a reduction in pulmonary artery pressure
for 1 h after the infusion.

15.4.2

ANP and hypoxia

In the last decade, since the first edition of this book,

there have been numerous reports of the effect of
hypoxia on the plasma levels of ANP at rest and on
exercise.
Ten minutes of severe hypoxia on isolated rat
and rabbit heart with constant flow perfusion
caused a fourfold increase in ANP released
(Baertschi et al. 1986). The same group found
increases in ANP blood levels in the whole animal
made hypoxic under anesthesia. There was great
variability in the response, which correlated with
the baseline central venous pressure, but not with
any other measured variables. Winter et al. (1989)
also found ANP levels to be increased by hypoxia in
the rat after 24 h but not after only 2 h. In patients
with chronic hypoxic lung disease, levels of ANP
were elevated and varied inversely with the Pa0z
(Winter et al 1987b).
In healthy volunteers Kawashima et al (1989)
studied the effect of 10 min of hypoxia at two levels;
15 per cent oxygen breathing produced no change,
but 10 per cent oxygen breathing increased ANP
levels by 15 per cent accompanied by an increase in
pulmonary artery pressure. Vonmoos et al. (1990)
found that 60 min of 12 per cent oxygen breathing
produced a small but significant elevation of ANP.
Lawrence et al (1990) found that the same hypoxic
stimulus produced a 50 per cent increase in ANP
levels in subjects on a low salt diet and whose
endogenous cortisol was suppressed with dexamethasone. Conversely, Ramirez etal (1992) did not
find a significant rise in ANP levels with either acute
(60 min) or chronic hypoxia at 3000 m, although the
ANP response to a sodium load was greater at
altitude. Antezana et al (1995) found a reduction in
ANP levels in lowlanders at 3600 m compared with
sea level and highlanders had significantly lower
ANP than lowlanders at altitude.

15.43

Exercise and ANP: normoxia

Somers et al (1986) found that a progressive exercise

test to maximum exercise resulted in an almost

184 Endocrine and renal systems at altitude

fourfold increase in plasma ANP with a decline to

baseline after 1 h at rest. Similar results have been
found for short-term exercise by Schmidt et al.
(1990) and by Lawrence and Shenker (1991). Hill
walking exercise for 5 days also resulted in elevated
ANP levels to about twice baseline values (Milledge
et al. 1991b). It is interesting to note that during this
type of exercise sodium is retained despite elevated
ANP levels.

15.4.4

Exercise and ANP: hypoxia

Mountaineers and trekkers going to altitude

normally have the double stimulus of exercise and
hypoxia. Schmidt etal. (1990) studied exercise while
breathing air or reduced oxygen (92 mm Hg). With
both maximal and submaximal exercise the ANP
response to exercise was reduced under hypoxic
conditions. In contrast, Lawrence and Shenker
(1991), using less severe hypoxia (16 per cent
inspired oxygen) and exercise such as to give a heart
rate of 70-75 per cent of maximum for 30 min,
found that hypoxia enhanced the ANP response. A
third study using a decompression chamber to give a
simulated altitude of 3000 m and a progressive exercise test to maximum showed a reduced response
(Vuolteenaho et al. 1992). The reasons for these differing results are not apparent.
Milledge et al. (1989) reported levels of plasma
ANP in 15 subjects before and after ascent on foot
from 3100 m to 4300 m. Values tended to be higher
at altitude but were significantly so only in the 4 a.m.
sample on the second altitude day, there being no
difference on day 1 at altitude or in the 9 a.m. sample
on either day. Bartsch et al. (199la) found, in blood
samples taken on the morning after the ascent to
4559 m on foot, no increase in ANP levels in a group
of nine climbers who did not have AMS. Five
subjects who did become sick had elevated levels.
These subjects had a history of HAPE and were
shown by echocardiography to have increased atrial
diameters at altitude. The increase in ANP is
probably secondary to developing high pulmonary
artery pressures. Kawashima et al. (1992) showed
that, in subjects susceptible to high altitude
pulmonary edema, breathing 10 per cent oxygen
resulted in a greater rise in ANP levels than in
controls, and that the rise correlated with the rise in
pulmonary artery pressure.

15.4.5

ANP and AMS

An important motive for the study of the effect of

altitude hypoxia on ANP has been the hypothesis
that it may play a part in the genesis of AMS.
Milledge et al. (1989) did not find any correlation
between levels of ANP on the morning after arrival at
altitude and the AMS symptom score. However,
Bartsch et al. (1988) and Cosby et al. (1988) found
subjects with AMS or HAPE to have higher levels
than subjects without AMS. If the rise in ANP in
AMS sufferers is related to high pulmonary arterial
pressure, elevation would be expected mainly in
AMS with pulmonary edema and not in the milder,
nonpulmonary cases. In the first-mentioned study
there was no clinical evidence of pulmonary edema.

15.4.6 ANP and chronic mountain

sickness
Antezana et al. (1995) have reported higher levels of
ANP in patients with chronic mountain sickness
(CMS) than in controls in Andean highlanders. In
this study pulmonary artery pressure was assessed by
Doppler ultrasound and found to be raised.
In conclusion, it seems that although both exercise
and hypoxia cause an elevation of ANP, the
combined stimulus does not result in very high levels
at altitude. Despite its name, ANP is not a powerful
natriuretic hormone. Levels of ANP are elevated in
conditions where the pulmonary artery pressure is
raised, including HAPE and polycythemia, and this
rise is presumably secondary to the raised pressure
causing some atrial enlargement. The rise in ANP is
probably beneficial in that it tends to reduce the
pressure by its vasodilatory function.
15.5

CORTICOSTEROIDS AND ALTITUDE

On ascent to altitude, there is stimulation of the

adrenal cortex by ACTH and cortisol is secreted.
Early work documented this as a rise in 17-hydroxycorticosteroids (17-OHCS) during the first few days
at altitude, which decreased to control values by days
5-7 (MacKinnon et al. 1963, Moncloa et al. 1965).
This has been confirmed by measurement of plasma
cortisol by Frayser et al. (1975) and Sutton et al.
(1977), who showed that with the elevation of

Ad renosympathetic system 185

plasma cortisol there was a decrease in its normal

diurnal variation on the first day of altitude
exposure. Richalet et al. (1989), in a chamber experiment, also found elevation of plasma cortisol with reestablishment of the diurnal variation after the first
altitude day. Many of the subjects of these studies,
taken rapidly to an altitude of 4300-5300 m, suffered
from AMS, but even those free of symptoms showed
this transitory rise in cortisol or its urinary
metabolite. It is assumed that this is a nonspecific
stress response.
CASE REPORT
An interesting case report shows that there is a
clinical lesson to be learnt. A 58-year-old man, who
had had his pituitary removed 10 years earlier for an
adenoma, went trekking in Nepal. On arrival at
Menang (3535 m) he complained of fatigue,
abdominal pain, nausea and vomiting, but no
headache. He was on regular medication with
cortisone 25 mg daily and had taken his treatment.
Twenty-four hours later he had deteriorated and was
unable to stand. He was treated with dexamethasone
5 mg i.v., 5 mg i.m. and oral rehydration, and his
cortisone dose was quadrupled. Within 24 h all
symptoms had disappeared, and the next day he
successfully crossed the Thorong La (5450 m)
(Westendorp et al. 1993). Clearly the lesson is that
subjects on corticosteroid replacement therapy
should increase their dosage on going to altitude.
The authors point out that this does not apply to
thyroid replacement therapy since thyroid stimulating hormone (TSH) is not increased by hypoxia.
The effect of prolonged stay at more extreme
altitude was studied by Siri et al. (1969). They
brought back urine samples from the 1963 Everest
expedition from climbers staying at 5400 m and
6500 m. The 17-OHCS levels were not significantly
different from sea level values. They also demonstrated a normal response to injected ACTH. Mordes
et al (1983) collected samples from subjects who had
been at 5400 m and 6300 m for some weeks and
found no change from sea level values in either
morning or evening cortisol concentrations.
In animals studied after chronic hypoxia there was
some hyperplasia of the adrenal cortex and of the
corticotrophic cells in the pituitary. No such
morphological changes have been found in humans
with long-standing chronic bronchitis (Gosney

1986). However, in subjects who had spent more

than 10 weeks above 6000 m, the cortisol level was
found to be three times normal (Anand et al. 1993).
Marinelli et al. (1994) studied athletes taking part in
a marathon race from 3860 m to 5100 m and down to
finish at 3400 m. Cortisol levels were similar at
altitude before the race but were greatly elevated at
the end.
In people resident at the moderate altitude of
2600 m in Columbia, Ramirez et al. (1995) found an
enhanced response to corticotrophin releasing
hormone, with higher levels of both ACTH and
P-endorphin after stimulation than in sea level
control subjects. This was true for a number of tropic
hormones (sections 15.7.1 and 15.9.2).

15.6
15.6.1

ADRENOSYMPATHETIC SYSTEM
Acute hypoxia

Acute hypoxia increases heart rate at rest and on

exercise (Maher et al. 1975b). This is presumed to be
due to increased sympathetic activity stimulating the
P-adrenergic receptors on heart muscle cell
membrane. However, measurements of plasma,
epinephrine and norepinephrine after 10 min of
mild isocapnic hypoxia at rest showed no increase
over control values despite a rise in heart rate from
70 to 83 beats/min-1 (Ind et al. 1984). On light exercise, plasma catecholamine levels are increased by
acute hypoxia, but this is not seen after heavy
exercise (75 per cent V02max) (Maher et al. 1975b).
Bouissou et al. (1989) also found a 32 per cent
increase in norepinephrine after 48 h at altitude but
on maximal exercise the rise in catecholamines was
no different from that seen at sea level. Mazzeo et al.
(1991) found reduced norepinephrine and raised
epinephrine levels at rest. On submaximal exercise,
norepinephrine levels rose as they did at sea level.
Epinephrine rose with exercise at altitude whereas it
remained unchanged at sea level.
15.6.2

Chronic hypoxia

Cunningham et al. (1965) reported elevated plasma

and 24-h urinary catecholamines during 17 days at
4559 m on Monte Rosa. There was no significant
change in epinephrine but the increase in norepi-

186 Endocrine and renal systems at altitude

nephrine was greater on day 12 at altitude. Pace et al.

(1964) found similar results at 3850 m, with urinary
norepinephrine excretion rising slowly during
14 days at altitude without change in urinary epinephrine secretion. Maher et al. (1975b) found
increased urinary catecholamines at 4300 m. Levels
were increased on day 1 compared with sea level and
further increased on day 11. On exercise, both light
and severe, the effect of chronic hypoxia compared
with acute was to increase levels still further. Hoon et
al. (1977) found no significant change in urinary
catecholamine secretion in a total of 76 subjects who
had no symptoms of AMS. However, in 29 symptomatic subjects there was a small but significant rise
on the first day at altitude, which was maintained
through to day 10 at altitude. Mazzeo et al. (1991)
found that, at rest, norepinephrine and epinephrine
levels were higher at altitude than at sea level. With
submaximal exercise, norepinephrine rose to higher
values than expected at sea level, whereas epinephrine levels did not rise, though values remained
above those at sea level. In Operation Everest II at
extreme altitude (282 mm Hg) after 40 days in the
chamber, resting plasma norepinephrine was raised
but epinephrine was reduced. On maximum
exercise, values for both catecholamines fell with
increasing altitude (Young et al. 1989).
In subjects who had spent more than 10 weeks
above 6000 m the plasma norepinephrine concentration was found to be almost three times normal
(Anand et al. 1993). Gosney et al. (1991) studied the
adrenal and pituitary glands of five lifelong residents
of La Paz who had lived at 3600-3800 m, and
compared their glands with those of controls from
sea level. The adrenal glands were significantly
bigger, by about 50 per cent. The pituitary glands
were not larger but contained more corticotrophs.
They surmised that greater amounts of ACTH were
required to maintain adrenal function, perhaps
because of hypoxic inhibition of adrenocortical
sensitivity. However, Ramirez et al (1988) found no
such inhibition.

15.63

Adrenergic response and

acclimatization
Acute hypoxia causes an increase in heart rate and
cardiac output. However, after several days at
altitude the heart rate and cardiac output fall back

towards sea level values. On exercise the maximum

heart rate is limited to well below the sea level
maximum, being typically 140-150 beats mur1 compared with 180-200 beats min^1 at sea level (Chapter
7). This reduction in maximal heart rate and cardiac
output takes place at a time when the plasma and
urinary catecholamines are higher than at sea level.
Evidently, the heart's response to sympathetic
stimulation becomes blunted. This has been demonstrated by Maher et al. (1975b), who showed in dogs
that the cardio-acceleratory effect of an infusion of
isoproterenol was reduced after 10 days' altitude
acclimatization. Workers from the same institution
(Maher et al. 1978) found in cardiac muscle of
acclimatized goats that there was a twofold rise of the
enzyme o-methyltransferase. This enzyme inactivates
cardiac norepinephrine, and its induction during
acclimatization may account for the blunting of the
adrenergic response to exercise. Another possibility
is that there may be downregulation, that is, a
reduction in the density of adrenergic receptors on
the heart muscle. Voelkel et al. (1981) have shown
this to be the case in rats kept for 5 weeks at a
simulated altitude of 4250 m. These two possible
mechanisms are not mutually exclusive. Sherpa high
altitude residents do not suffer this heart rate
limitation on maximal exercise. Their heart rates can
go up to 190-198 beats mhr1 at 4880 m (Lahiri et al.
1967).
In summary, hypoxia has no effect on epinephrine
levels in the blood or urine but there is a modest rise
in norepinephrine levels. This may be more marked
in subjects with AMS. The response of the heart to
adrenergic stimulation becomes blunted after a week
or 10 days at altitude and this is probably due to
downregulation of receptors and induction of the
enzyme responsible for catecholamine metabolism.

15.7
THYROID FUNCTION AND THE
ALTITUDE ENVIRONMENT
Hypothalamic-pituitary-thyroid axis function is
affected by hypoxia and possibly by cold. The effect
of cold on thyroid function is considered in Chapter
24. Iodine is essential for synthesis of thyroid
hormone and is deficient in the soil and water of
some mountainous regions, so that thyroid function
in residents of these regions is affected.

Control of blood glucose at altitude 187

15.7.1

Thyroid function and hypoxia

The response of the hypophyseal-thyroid axis to

hypoxia seems to be quite different in humans
compared with animals. In animals, hypoxia results
in depression of thyroid function (Heath and
Williams 1995, pp. 265-6). In the pituitary gland the
number of thyrotrophs - cells that secrete TSH - is
reduced, suggesting a decreased output of TSH
(Gosney 1986). In humans, however, thyroid activity
is increased at altitude. Surks (1966) found elevated
levels of thyroxine binding globulin (TBG) and free
thyroxine (T4) in the first 2 weeks at altitude
(4300 m), with a peak at 9 days. Kotchen et al.
(1973), in a 3-day chamber experiment (3650 m
equivalent), found T4 elevated (free and bound) but
TSH to be unchanged, suggesting a shift of T4 from
extravascular to intravascular compartments rather
than increased pituitary activity. Westendorp et al.
(1993) also found no increase in TSH in response to
a 1-h acute hypoxia equivalent of 4115 m.
These results have been confirmed in a number of
field studies (Rastogi et al. 1977, Stock et al. 1978b)
which showed levels returning towards control in the
third week at altitude. Sawhney and Malhotra (1991)
studied both acclimatized lowlanders and high
altitude natives, and found levels of triiodothyronine
(T3) and T4 to be higher than sea level residents. T4
concentration in red cells was decreased at high
altitude but there was no change in levels of reverse
T3 (rT3), TBG, and T4 binding capacity of TBG and
thyroxine binding prealbumin. They also found no
change in TSH. In i-eltroxine-treated men they still
found a rise in T3 and T4, suggesting the rise to be
independent of pituitary stimulation.
Exercise increases T3 and T4 to a greater extent at
altitude than at sea level (Stock et al. 1978b). At
higher altitudes of 5400 m and 6300 m, Mordes et al.
(1983) showed elevated resting T3, free T4 and T3 in
subjects who had been at altitude for some weeks. In
these subjects TSH was also elevated, in contrast to
the finding at lower altitudes.
The basal metabolic rate is elevated during the first
2 weeks at moderate altitude and correlates with the
free T4 (Stock et al. 1978a). At higher altitudes (above
5500 m) it remains elevated for months (Gill and
Pugh 1964), as does T4 (Mordes et al. 1983). Mordes
etal. (1983) also found evidence of impaired conversion of T4 to T3 at 6300 m. Perhaps there is a change in
the set point for the pituitary negative feedback

system, resulting in higher levels of TSH. They also

found that the response of the pituitary to an injection of thyrotrophin releasing hormone was
enhanced at 6300 m compared with sea level.
Recently a similar finding has been reported (Ramirez
et al. 1995) in resident highlanders at only 2600 m.

15.7.2 Iodine deficiency, goitre and

altitude
The frequency of goitre in mountainous areas is well
known and is discussed in Chapter 17. In England it
was known as 'Derbyshire neck' and it was equally
well known in the Pyrenees, the Alps, the Andes and
the Himalayas, but it is not confined to the
mountains.
The association of iodine deficiency and
mountainous areas is mainly due to the geological
factors (Chapter 17) but altitude hypoxia stimulates
thyroid function (section 15.7.1). Thus the effect of
iodine deficiency will result in more exaggerated
hyperplasia, which contributes to the extremely high
rate of goitre in resident populations at altitude.

15.8
CONTROL OF BLOOD GLUCOSE AT
ALTITUDE

15.8.1

Acute hypoxia

On acute exposure to hypoxia there is a rise in fasting

blood glucose of about 1.7 mmol L"1, followed by a
fall towards control values by the end of a week. At
the same time insulin levels are elevated (Williams
1975). This is presumably part of the nonspecific
stress response indicated by the concurrent rise in
plasma cortisol levels (section 15.5).

15.8.2

Chronic hypoxia

In subjects acclimatized to high altitude, fasting

blood glucose was found to be lower than at sea level
by some workers (Blume and Pace 1967, Stock et al.
1978b, Blume 1984) but unchanged by others
(Sawhney et al. 1986). Singh et al. (1974) found a
persistently raised glucose level after 10 months at

188 Endocrine and renal systems at altitude

altitude. Resting insulin levels have also been found

to be reduced (Stock et al. 1978b).
Glucose loading increases both blood glucose and
insulin levels at altitude as it does at sea level, but the
rise in both was found to be less than at sea level in
two studies (Stock et al 1978b, Blume 1984) but
greater in one (Sawhney et al. 1986). There are a
number of explanations for this blunted response.
Glucose may be absorbed less rapidly, though this is
probably only true above about 5500 m (section
14.5). Liver glycogen synthesis may be enhanced at
altitude and some evidence for this has been found in
rats injected with labeled glucose at altitude (Blume
and Pace 1971). There maybe increased target organ
sensitivity to insulin, presumably by upregulation
(increased density) of insulin receptors on target
cells. This is a feature of athletic training and may
well happen as part of altitude acclimatization.
Braun et al. (1998) studied the glucose response to
a standard meal in women at sea level and at 4300 m
in the presence of estrogen (E) and estrogen plus
progesterone (E+P). The peak of glucose was lower
and returned to baseline more slowly at altitude than
at sea level although the insulin levels were the same.
The response was also lower in E than E+P at sea
level but the difference at altitude was not significant.
It would seem that at altitude the relative concentration of ovarian hormones does not appear to be
important in glucose control.

15.9
15.9.1

ENDOTHELIN
Endothelin family

The endothelins are a family of peptides produced by

a wide variety of cells affecting mainly blood vessels.
Endothelin-1 (ET-1), clinically the most important
member of the family, is the most potent vasoconstrictor yet discovered with about 100 times the
activity of norepinephrine. Other members of the
family identified are ET-2 and ET-3, which are more
localized to certain organs. All three peptides bind to
the same two receptors, A and B, though with differing binding affinities. Synthetic inhibitors of these
receptors are now available and their use has served
to elucidate some of the actions of these peptides.
ET-1 is produced by the endothelium and as much as
75 per cent of the production is exported from the

side of the cell opposite to the vessel lumen, where it

acts on the adjacent smooth muscle without
contributing to the plasma pool. In this way it
perhaps should be considered as mainly a paracrine,
rather than an endocrine, hormone. However,
plasma levels probably do reflect the output of ET-1
and parallel the severity of the condition in, for
instance, congestive cardiac failure.
A good clinical review has been published by Levin
(1995), and Holm (1997) has provided a more
pharmacological review.

15.9.2

Altitude and endothelin

Horio etal. (1991) showed that ET-1 in rats increased

with increasing hypoxia. Since then there have been a
number of studies in humans at altitude. Cargill et al.
(1995) found that 30 min of acute hypoxia (Sa^
75-80 per cent) raised plasma ET-1 levels to about 2.5
times baseline. A group of hypoxic patients with cor
pulmonale had similar levels. Similar results were
found by Ferri et al. (1995) in patients with chronic
obstructive lung disorder (COLD). They also found
that ET-1 levels correlated with pulmonary artery
pressure. Morganti etal. (1995) studied 10 subjects on
a 2-day ascent of Monte Rosa (4559 m) and eight subjects in the Everest region at 5050 m. They found
plasma ET-1 raised progressively with increasing altitude, the level correlating with the fall in 5ao2. There
was no correlation with blood pressure or hematocrit.
Richalet and colleagues (1995) studied 10 subjects on
Sajama (6542 m) and found modest increases in ET-1
at both rest and exercise. Levels were highest after
1 week and decreased slightly after 3 weeks' altitude
exposure. A Japanese group (Droma et al. 1996a)
reported detailed findings on a single case of HAPE
with pulmonary hypertension and found ET-1 levels
elevated on admission. The levels reverted to normal
as the patient recovered and pulmonary artery
pressure fell. The same team (Droma 1996b) studied a
group of HAPE-susceptible subjects. Their subjects
had a greater hypoxic vascular response than controls
but no significant change in ET-1 levels with a
hypoxic challenge. However, the hypoxia was only of
5-min duration (10 per cent oxygen). Blauw et al.
(1995) studied the effect of hypoxia and ET-1 infusion
on forearm blood flow. Forearm blood flow was not
changed by hypoxia, but the ET-1 plasma increased
significantly. They conclude that hypoxia causes

Altitude and other hormones 189

release of ET-1 from the pulmonary circulation but

that this does not influence peripheral vascular tone.
Cruden et al. (1998) measured both ET-1 and big
ET-1 in a group of mountaineers. Both were increased
on ascent to altitudes above 2500 m, indicating that
the increase in ET-1 was due to increased production
and not decreased elimination. After 3 weeks at
altitude, levels had returned to baseline values.
Exercise had no effect on endothelin levels. In a
separate study, they also found increases in both ET-1
and big ET-1 with cold exposure (Cruden et al. 1999).
In conclusion, it seems likely that ET-1 plays a part
in the mechanism of hypoxic pulmonary vasoconstriction, at least in the pig (Holm 1997). Whether
it has a role in the mechanism of high altitude
pulmonary edema remains to be determined.

15.93

Bradykinin

The levels of bradykinin, a potent vasodilator, are not

changed by acute hypoxia (Ashack et al. 1985),

15.10
ALTITUDE AND OTHER
HORMONES
15.10.1

Glucagon

Fasting glucagon levels are the same at altitude and at

sea level and are slightly depressed after glucose loading (Blume 1984).
15.10.2

Growth hormone

Levels are unchanged in most subjects but were

found to be increased fivefold in two subjects who
had lost 15 kg in body weight (Blume 1984).
Although acute hypoxia causes no change in growth
hormone levels, exercise under acute hypoxic conditions causes a 20-fold increase in this hormone,
whereas normoxic exercise causes only a modest rise
(Sutton 1977, Raynaud et al. 1981). Ramirez et al.
(1995) studied residents at Pasto, Columbia
(2600 m), and found that response of growth
hormone to stimulation with growth hormone
releasing hormone was greatly enhanced compared
with lowland control subjects.

15.10.3 Testosterone, luteinizing

hormone, follicle stimulating hormone
and prolactin
Sawhney et al. (1985) studied levels of testosterone,
luteinizing hormone (LH), follicle stimulating
hormone (FSH) and prolactin in lowland men after
ascent to 3500 m. On day 1 at altitude there were no
significant changes from sea level values, though LH
and testosterone levels were already falling. By day 7,
LH and testosterone levels were significantly reduced
and remained so to day 18; by then prolactin levels
were significantly elevated. After 7 days at sea level all
values had reverted to control except for some residual depression in LH levels. These results are in
accord with previous work (Guerra-Garcia 1971)
which found urinary testosterone excretion to be
reduced by 50 per cent on day 3 at 4300 m. Sawhney
et al. (1985) also found a negative correlation
between prolactin and testosterone levels at altitude
but no correlation with LH levels. They suggested
that the reduction in testosterone is due to increase
in prolactin secretion rather than to a reduction in
LH or a direct effect of hypoxia on the testes.
In a separate experiment at sea level Sawhney et al.
(1985) showed a reduction in LH levels in response
to daily cold exposure after 1 and 5 days, and
suggested that the reduction in LH found at altitude
might be due to cold rather than hypoxia. However,
low levels of LH have been found in hypoxia due to
chronic lung disease in hospital patients with no cold
exposure (Semple 1986); these patients also had low
testosterone levels which correlated with their Pa02.
Semple (1986) found normal testosterone levels in
patients who were hypoxic because of congenital
cardiac defects, presumably because of lifelong
adaptation to hypoxemia. He suggests that an alternative mechanism may be that testosterone depression is a response to dips in oxygen saturation at
night, due to sleep apnea in patients with chronic
obstructive lung disease, and a result of periodic
breathing in lowlanders at altitude. In high altitude
residents, Bangham and Hackett (1978) found
reduced levels of LH after 10 days but no changes in
levels of FSH, testosterone or prolactin.
Testosterone is increased in exercise and Bouissou
et al. (1986) studied the effect of acute hypoxia
(14 per cent oxygen, equivalent to 3000 m) on this
response. They found that, when the exercise was
expressed as a percentage of maximum exercise,

190 Endocrine and renal systems at altitude

there was no effect of acute hypoxia. This is also true

for the acute hypoxic effect on the exercise-induced
rises of lactate, epinephrine and norepinephrine.

15.11

15.11.1

RENAL FUNCTION AT ALTITUDE

General function

The kidney is remarkably resistant to altitude

hypoxia. This is not surprising since it is designed to
suffer quite severe reductions in blood flow, and
therefore oxygen delivery, during exercise. At
5800 m, after 24-h dehydration, the kidney concentrates urine normally and eliminates a water load as
well as it does at sea level. It also responds to
ingestion of bicarbonate or ammonium chloride
(metabolic alkalosis or acidosis) by producing
appropriate changes in pH (Ward, reported by Pugh
1962a). Olsen et al. (1993) found a 10 per cent
reduction in effective renal plasma flow (ERPF) but
normal glomerular filtration rate and sodium clearance in eight normal subjects at 4350 m. Dopamine
infusion had less effect on ERPF than at sea level,
presumably because of increased adrenergic activity
(norepinephrine was increased). The diuretic effect
of dopamine was reduced, possibly because of an
altitude effect on distal tubular function. High
altitude residents at 4300 m showed no evidence of
deficient renal oxygenation (Rennie etal 1971a).
However (as discussed in section 9.4.5), at extreme
altitude (above 6500 m) the renal compensation for
respiratory alkalosis is slow and incomplete; that is,
the blood bicarbonate is very little further reduced
and the blood pH becomes very alkaline as the PCOz is
reduced by extreme hyperventilation. Whether this
represents a degree of renal failure is debatable, since
it results in a shift of the oxygen dissociation curve to
the left (because of the alkaline pH), which is
beneficial for oxygen transport at extreme altitude
(section 9.3.6).

15.11.2

15.4 shows that there is a good correlation between

the degree of proteinuria and altitude, provided
allowance is made for a 24-h time lag between ascent
and its effect on the kidney.
In another study, Rennie et al. (1972) found no
effect of acclimatization on proteinuria but Pines
(1978) found less proteinuria on repeat ascents to the
same altitude, and also that subjects with AMS had
the greatest proteinuria. High altitude residents
excrete more protein in the urine than subjects of the
same race at sea level (Rennie et al. 1971b).
Patients with cyanotic heart disease who are
chronically hypoxic from birth also have increased
proteinuria, the severity being directly related to the
degree of polycythemia (and hypoxia) (Rennie
1973); it is also found in patients with chronic
obstructive lung disease (Wilkinson etal. 1993).
Bradwell and Delamere (1982) studied the effect
of acetazolamide on altitude proteinuria as part of a
double blind trial of the drug as a prophylactic for
AMS. They found that, at 5000 m, albuminuria was
six times greater in subjects on placebo tablets than
in those on acetazolamide. They found an inverse
correlation between Pa02 and percentage increase in
urine albumin. The eight subjects on acetazolamide
were of course less hypoxic, with Pa02 > 42 mm Hg,
than nine subjects on placebo with Pa02 < 42 mm Hg.
The authors suggest that the effect of acetazolamide
on albuminuria was due to this reduction in hypoxia.
The mechanism for altitude proteinuria may be
either a reduction in tubular reabsorption of protein
or increased glomerular permeability to protein, or
both.

Proteinuria at altitude

Rennie and Joseph (1970) showed that proteinuria

became apparent on ascent to altitude. Values rose
from 290 to 578 jig mmoh1 as their subjects climbed
to 5800 m in 12 days. There was a time lag of 1-3 days
between peak altitude and peak proteinuria. Figure

Figure 15.4 Proteinuria at altitude, the altitude being that of the

subjects 24 h before urine sampling. (After Rennie 1973.)

16
Central nervous system
16.1
16.2
16.3
16.4

Introduction
Historical
Mechanisms of action of hypoxia
Central nervous system function at
high altitude

191
192
192
195

SUMMARY
The central nervous system (CNS) is exquisitely sensitive to hypoxia and so it is not surprising that
impairment of neuropsychological function can be
demonstrated at high altitude. Brain oxygenation is a
function of both arterial P02 and cerebral blood flow.
The latter is regulated in part by the arterial blood
gases. Hypoxemia causes cerebral vasodilatation
whereas a reduced arterial PC02 results in cerebral
vasoconstriction: these are therefore conflicting factors at high altitude. Some impairment of neuropsychological function, for example slow learning of
complex mental tasks, can be demonstrated at altitudes of less than 2000 m. At higher altitudes many
aspects of neuropsychological function have been
shown to be impaired, including reaction time,
hand-eye coordination, and higher functions such as
memory and language expression. Several studies
have documented residual impairment of neuropsychological function after ascents to very high altitude. An interesting finding is that climbers with a
high hypoxic ventilatory response tend to have the
most severe residual impairment, possibly because
the associated reduced arterial Pcc,2 causes cerebral
vasoconstriction and therefore more severe cerebral
hypoxia. Oxygen enrichment of room air improves
neuropsychological function at an altitude of 5000 m

16.5 Residual central nervous system impairment

following return from high altitude
16.6 Effect of oxygen enrichment of room
air on neuropsychological function at
high altitude

198
200

and may therefore improve performance in commuters to mines and telescopes.

16.1

INTRODUCTION

Of all the parts of the body, the CNS is one of the

most vulnerable to hypoxia. It is not surprising,
therefore, that people who go to high altitude often
have changes in neuropsychological function,
including special senses such as vision, higher functions such as memory and affective behavior such as
mood. Such changes have been observed in individuals acutely exposed to hypoxia, in lowlanders
sojourning at high altitude, and in high altitude
natives.
In addition to the changes in neuropsychological
function seen in individuals at high altitude, there is
mounting evidence that there may be persistent
defects of CNS function on return to sea level after
periods of severe hypoxia at high altitude. These
findings are of special interest now because increasing numbers of climbers choose to climb at great altitudes without supplementary oxygen. Many people
are concerned about the increase in morbidity and
mortality on expeditions to extreme altitude, and
irrational decisions made by severely hypoxic
climbers probably play an important role.

192 Central nervous system

16.2

HISTORICAL

Changes in mood and behavior at high altitude have

been recognized from the early days of climbing high
mountains. However, the most extreme effects of
hypoxia on the CNS were seen by the early balloonists where partial paralysis, difficulties with vision,
mood changes and even loss of consciousness are
well documented. For example, during the famous
flight of the balloon 'Zenith' by Tissandier and his
two companions (Tissandier 1875) we read,
towards 7500 metres, the numbness one experiences is extraordinary. . . . One does not suffer at
all; on the contrary. One experiences inner joy, as if
it were an effect of the inundating flood of light.
One becomes indifferent

This lack of appreciation of the dangers of acute

hypoxia is well known to aircraft pilots and is the reason why there are stringent regulations on using oxygen above certain altitudes despite the fact that the
pilot may not feel that he needs it.
The paralysing effects of hypoxia were vividly
described during the balloon ascent by Glaisher and
Coxwell in 1862 (Glaisher et al. 1871). At the highest
altitude, Glaisher collapsed unconscious in the basket and it was left to Coxwell to vent the hydrogen
from the balloon to bring it down. However, Coxwell
had apparently lost the use of his hands and instead
had to seize the cord that controlled the valve with
his teeth and dip his head two or three times.
Incidentally, this flight also underscored the rapid
recovery from severe acute hypoxia. When the balloon landed, Glaisher stated that he felt 'no inconvenience' and they both walked between 7 and 8
miles to the nearest village because they had come
down in a remote country area.
When climbers began to reach great altitudes,
neuropsychological disturbances were frequently
reported. For example, there were several descriptions of bizarre changes in perception and mood on
the early expeditions to Mount Everest. During the
1933 Everest expedition, Smythe gave a dramatic
description of a hallucination when he saw pulsating
cloud-like objects in the sky (Ruttledge 1933).
Smythe also reported a strong feeling that he was
accompanied by a second person; he even divided
food to give half to his nonexistent companion. On
occasions, the changes in CNS function suggest

attacks of transient cerebral ischemia. For example,

the very experienced mountaineer, Shipton, had a
remarkable period of aphasia at an altitude of about
7000 m on the same expedition (Shipton 1943). He
reported that 'if I wished to say "give me a cup of
tea", I would say something entirely different maybe "tram-car, cat, put" ... I was perfectly clearheaded ... but my tongue just refused to perform
the required movements....'
In the last few years there has been increasing
interest in the neuropsychological effects of high altitude. For example, the Polish climber and psychiatrist Ryn found a range of psychiatric disturbances in
mountaineers who had ascended to over 5500 m
(Ryn 1971). He also reported that symptoms similar
to an organic brain syndrome persisted for several
weeks after the expedition. Some climbers had
electroencephalogram abnormalities after climbs to
great altitudes. Studies made during the war between
China and India in the early 1960s, when Indian
troops were rapidly airlifted to high altitude, showed
residual changes in psychomotor function on return
to sea level (Sharma et al. 1975, 1976). Townes et al.
(1984) made measurements on members of the
American Medical Research Expedition to Everest
(AMREE) after they had returned to sea level following about 3 months at altitudes of 5400-8848 m and
found residual abnormalities of neuropsychological
performance. Similar results were found on
Operation Everest II, including the additional interesting observation that climbers with the highest
hypoxic ventilatory response were more severely
affected. There have been steady improvements in
the techniques of neuropsychological testing and it is
becoming clear that minor changes in function are
extremely common at high altitude, and that some
residual impairment often remains in some climbers
who return to sea level from great altitudes.

163
MECHANISMS OF ACTION OF
HYPOXIA
16.3.1

Hypoxia and nerve cells

Despite a great deal of research over the last few

decades, a clear understanding of the effect of
hypoxia on nerve cells remains elusive (Siesjo

Mechanisms of action of hypoxia 193

1992a,b, Haddad and Jiang 1993, Hossmann 1999).

Mild hypoxia accelerates glucose utilization by nerve
cells, but utilization is depressed during severe
hypoxia. Within the brain, the hippocampus, white
matter, superior colliculus and lateral geniculates
appear particularly sensitive to levels of oxygen.
Brain lactate levels increase in early stages of hypoxia.
Brain tissue concentrations of ATP, ADP and AMP
apparently remain close to normal even during
severe hypoxia.
Altered ion homeostasis during hypoxia clearly
occurs, though whether the ionic changes are primary, or whether they are due to altered oxidative or
neurotransmitter metabolism, is unclear. Hypoxia
interferes with calcium homeostasis. For example,
very low oxygen levels diminish calcium uptake at
synapses. One hypothesis is that the decrease of calcium in the endoplasmic reticulum is a critical factor
(Paschen 1966). Intracellular levels of potassium are
increased during severe hypoxia. There is accumulation of free radicals which cause further injury, particularly to the capillaries. Neurotransmitter
metabolism is thought to be sensitive to hypoxia
although there is conflicting evidence about which
transmitter or metabolic step is most sensitive. There
is evidence that acetylcholine synthesis by brain is
oxygen dependent, as is the biosynthesis of amino
acid neurotransmitters. Brain catecholamine concentrations are apparently decreased by hypoxia
though the mechanism is unclear. Much of the
experimental work has been done on ischemia, and
the relationship of the changes to those caused by
pure hypoxia is controversial.
The effects of hypoxia on brain synapses and
membrane polarization interfere with the normal
electrical activity of the brain and alter the electroencephalogram (EEC). In cats in which the arterial
P02 is gradually reduced from 80 to 20 mm Hg, the
EEC amplitude initially increases slightly and then
slow waves and sharp spikes appear. Subsequently
the slow waves decrease in amplitude and then disappear. Later these small spikes become sporadic and
finally the EEC flattens. The initial activation which
is followed by depression may be due to the effect of
hypoxia on the reticular activating system.
Evoked potentials are also altered by hypoxia.
Brainstem auditory response is abolished by low levels of oxygen. Visually evoked potentials are initially
increased and then abolished as the level of oxygen is
reduced.

Histological changes in the brain result from

severe hypoxia. The changes are indistinguishable
from those due to hypotension and the greatest
changes are seen in the cortex and basal ganglia.
Microvacuolation of neuronal perikaryon occurs
first, the HI zone (Sommer sector) of the hippocampus being the most vulnerable region.

163*2

Cerebral blood flow

The levels of arterial P02 and PC02 have crucial effects

on cerebral blood flow and since these levels are
greatly altered by going to high altitude, the results
are important. Arterial hypoxemia dilates cerebral
blood vessels and greatly increases cerebral blood
flow. Figure 16.1 shows typical results found in anesthetized normocapnic rats. It can be seen that cerebral blood flow was little changed until the arterial
P02 fell below 60 mm Hg but with lower levels of P02
there was a dramatic increase in cerebral blood flow.
Note that at an arterial P02 of 25 mm Hg, cerebral
blood flow was approximately five times the normoxic level. As indicated in Chapter 12, the arterial
PO2 of a climber resting on the summit of Mount
Everest is 25-30 mm Hg.

Figure 16.1 Effect of changes of arterial P02 on cerebral blood flow

(CBF) in anesthetized rats. The arterial PC02 was maintained
normal. Note the very sharp rise in blood flow as the arterial P02
was reduced below 50 mm Hg. (From Borgstrom et al. 1975.)

194 Central nervous system

The results shown in Figure 16.1 were obtained in

mechanically ventilated animals where PC02 was kept
constant at the normoxic level. However, in conscious animals and humans, the hyperventilation
caused by the hypoxemia will cause a reduction in
arterial PC02 and an increase in pH which will cause
cerebral vasoconstriction. Therefore the results
shown in Figure 16.1 cannot be applied directly to
the climber at extreme altitude.
A reduction in arterial Pcc,2 has a strong vasoconstrictor effect on cerebral blood vessels and consequently reduces cerebral flood flow. Figure 16.2
shows typical results in mechanically ventilated anesthetized dogs which were made hypocapnic by
increasing the ventilation, or hypercapnic by adding
carbon dioxide to the inspired gas. In every instance
the arterial P02 was maintained at approximately the
normal level. Note that when the arterial PC02 fell to
about 15 mm Hg, cerebral blood flow was reduced by
about 40 per cent (Harper and Glass 1965).
In humans at high altitude, the two effects of
hypoxemia and hypocapnia will clearly have opposing
effects on the cerebral circulation. There have not
been systematic studies of cerebral blood flow at various altitudes, partly because of the difficulties of
measurement. However, Severinghaus et al. (1966b)
measured cerebral blood flow in seven normal subjects by a nitrous oxide method at sea level and after

Figure 16.2 Effect of alterations in arterial PC02 on cerebral

cortical blood flow in anesthetized dogs. The zero reference line for
blood flow is at an arterial PC(,2 of 40 mm Hg. Animals were
normoxic and normotensive. (From Harper and Glass 1965.)

6-12 h and 3-5 days at an altitude of 3810 m. The

blood flow increased by an average of 24 per cent at
6-12 h, and by 13 per cent at 3-5 days at altitude.
Acute correction of the hypoxia restored the cerebral
blood flow to normal. Extrapolation of additional data
suggested that if the PC02 had not been reduced at high
altitude, the cerebral blood flow would have been
60 per cent above the control. An interesting feature of
the data obtained by Severinghaus et al. (1966b) is that
a subsequent analysis shows that oxygen delivery to
the brain (as calculated from cerebral blood flow multiplied by arterial oxygen concentration) was held
essentially constant (Wolff 2000). However, there is
no known receptor that responds to oxygen delivery.
Indirect evidence about cerebral blood flow in
humans can be obtained by measuring blood flow
velocity in the internal carotid artery by Doppler
ultrasound. Huang etal. (1987) measured flow velocities in the internal carotid and vertebral arteries in six
subjects within 2-4 h of arrival on Pikes Peak
(4300 m) in Colorado, and found that the velocities
in both arteries were slightly increased above sea level
values; 18-44 h later, a peak increase of 20 per cent
was observed. However, over days 4-12, velocities
declined to values similar to those at sea level. In the
further study by the same group (Huang et al. 1991)
the effect of prolonged exercise (45 min at approximately 100 W) on blood flow velocity in the internal
carotid artery was studied at sea level and at 4300 m.
The velocities at sea level and high altitude were similar. In a low pressure chamber study, Reeves et al.
(1985) measured blood flow velocity in the internal
carotid artery of 12 subjects at Denver (1609 m) and
repeatedly up to 7 h at a simulated altitude of 4800 m.
Their hypothesis was that an increase in blood flow
velocity might be associated with the development of
high altitude headache, but no correlation was found.
Other studies by Doppler ultrasound have shown no
correlation between cerebral blood flow and acute
mountain sickness (Baumgartner etal. 1999), or cerebral blood flow and susceptibility to high altitude pulmonary edema (HAPE) (Berre et al. 1999). On the
other hand, Jansen etal. (1999) reported that subjects
with acute mountain sickness (AMS) had higher cerebral blood flows than normals, and also a greater
hemodynamic response to hyperventilation.
Huang et al. (1992) measured blood flow velocity
in the internal carotid arteries of 15 native Tibetans
and 11 Han Chinese residents of Lhasa (3658 m)
both at rest and during exercise. There were no

Central nervous system function at high altitude 195

differences at rest and during submaximal exercise.

At peak exercise, the Tibetans showed an increase in
flow velocity and cerebral oxygen delivery whereas
the Hans did not. Frayser et al. (1970) measured the
mean circulation time through the retina following
fluorescein injection and found that the circulation
time decreased from a mean of 4.9 s at base camp to
3.4 s at an altitude of 5330 m. This is consistent with
an increase in cerebral blood flow.
Another possible factor at high altitude which
could influence cerebral blood flow is an increased
viscosity of the blood caused by polycythemia.
Although this has not been specifically studied, it is
known that a blood flow of less than half the normal
value can occur in severe polycythemia vera (Kety
1950) and that cerebral blood flow is significantly
increased in severe anemia (Heyman et al. 1952,
Robin and Gardner 1953). Some drugs, including
caffeine, reduce cerebral blood flow.
Recently, interesting observations on brain oxygenation at high altitude were obtained by Imray and
colleagues (2000) who studied members of a climbing expedition in the Andes. They used near-infrared
spectroscopy which allows measurements to be made
through the skull. The signal comes from the hemoglobin in the brain blood, and although it includes
some arterial blood, it is apparently heavily weighted
towards the capillary and venous saturation, and
therefore probably gives a useful measure of trends in
the oxygenation of brain tissue. The most interesting
results were found using voluntary hyperventilation.
At sea level, hyperventilation caused a fall in oxygen
saturation presumably because of the reduction in
blood flow. However, at an altitude of 3560 m, there
was no change in oxygen saturation by this technique, and at the higher altitude of 4680 m, the saturation increased. Presumably the explanation is that
at the higher altitude, the increase in arterial oxygen
saturation had more effect on brain oxygenation
than the reduction of cerebral blood flow.

16.4
CENTRAL NERVOUS SYSTEM
FUNCTION AT HIGH ALTITUDE

16.4*1

Moderate altitudes

There is general agreement that CNS function is

impaired at altitudes over about 4500 m, but an

interesting question concerns the lowest altitude at

which minor alterations in function occur. This
question frequently arises in the aviation industry
because it is important in selecting the cabin pressure
of commercial aircraft. Most high flying commercial
aircraft are pressurized to maintain the cabin pressure at or below an equivalent altitude of about
2500 m. This ceiling was accepted after considering
the penalty of extra weight and expense which would
have to be paid in order to reduce it further.
However, there is some evidence that at a pressure
equivalent to an altitude of 2440 m, subjects are
slower to learn complex mental tasks than at sea
level. Even at the considerably lower altitude of only
5000 ft (1524 m), eight subjects were slower to learn
complex tasks than a matched group breathing an
enriched oxygen mixture (Denison et al. 1966). The
tests here involved recognizing the posture of
human-like figures having different orientations and
presented in random sequence on a screen. Thus it
appears that even at the cabin altitudes of commercial aircraft, sensitive psychometric tests can pick up
minor degrees of impairment.
Interesting problems concerning CNS function at
moderate altitudes occur in relation to the operation
of optical and infrared telescopes on mountain summits (see also Chapter 29). The reduction in the
absorption of optical and infrared radiation because
of the reduced thickness of the Earth's atmosphere at
high altitude makes high mountains ideal locations
for astronomical observatories. For example, several
telescopes are located on the summit of Mauna Kea
(4200 m), on the island of Hawaii.
The barometric pressure on the summit of Mauna
Kea is only about 468 mmHg, giving a moist
inspired P02 of 88 mm Hg. The telescope operators
frequently live at sea level and ascend rapidly by car
to the summit. Forster (1986) measured arterial
blood gases on 27 telescope personnel on the first day
of reaching 4200 m and reported a mean arterial P02
of 42 mm Hg, PC02 29 mm Hg and pH 7.49. After
5 days, during which time the nights were spent in
dormitories at an altitude of 3000 m, the arterial
blood gases at 4200 m showed a mean P02 of
44 mm Hg, Pcc,2 27 mm Hg and pH of 7.48.
A number of psychometric measurements showed
no change on ascending to 4200 m, though performance of the digit symbol backwards test did deteriorate on the first day. At the end of 5 days, however, the
scores had returned to sea level values. Numerate

196 Central nervous system

memory and psychomotor ability were also reported

to be impaired in commuters to Mauna Kea. Several
features of AMS were noted in shift workers, particularly on their first day at the summit. Headache was the
most disabling symptom but others included insomnia, lethargy, poor concentration and poor memory.

16.4.2

High altitudes

A classical series of studies was carried out by

McFarland (1937a,b, 1938a,b) in connection with the
International High Altitude Expedition to Chile which
took place in 1935. In his first study, McFarland
reported on the psychophysiological effects of sudden
ascents to 5000 m in unpressurized aircraft and compared the results with ascents by train and car to villages as high as 4700 m in Chile. The measurements
showed that the rate of ascent was an important variable, with the rapid increase in altitude by aircraft
being the most damaging. Both simple and complex
psychological functions were significantly impaired at
high altitudes including arithmetical tests, writing
ability, and the appearance and disappearance time of
after-images following exposure of the eye to a bright
light. There were increased memory errors, errors in
perseverance, and reductions in auditory threshold
and words apprehended.
In a second study of sensory and motor responses
during acclimatization, when measurements were
obtained at altitudes as high as 5330 and 6100 m, significant reductions in audition, vision, and hand-eye
coordination were seen. Measurements were made at
several altitudes but in general, impairment of function was not significant below an altitude of 5330 m.
Again members of the expedition with the longest
periods of acclimatization appeared to suffer less
deterioration.
In a further study, mental and psychosomatic tests
were also administered at the same altitudes and these
showed deterioration. Tests involving the quickness
of recognizing the meaning of words, mental flexibility or tendency to perseveration, and immediate
memory showed significant impairment. It was noted
that complex mental work could be carried out if the
subjects increased their concentration but in general
there was increased distractibility and lethargy which
tended to reduce the ability to concentrate.
In a final series of measurements, sensory and circulatory responses were measured on sulfur miners

residing permanently at an altitude of 5330 m at

Aucanquilcha in Chile. They were compared with a
group of workmen at sea level who were similar in
age and race, and also with members of the expedition. It was found that the miners at high altitude
were slower in simple and choice reaction times and
less acute in auditory sensitivity than the workmen at
sea level. However, McFarland and his colleagues
were impressed by the evidence for circulatory and
respiratory adaptation in these permanent residents
at an altitude of 5330 m.
More recently, additional studies on the deleterious effects of acute hypoxia on visual perception
have been carried out, partly because of the importance of this topic in aviation. For example, Kobrick
(1975) documented impaired response times in the
detection of flash stimuli at equivalent altitudes of
sea level, 4000 m, 4600 m and 5200 m during acute
exposure in a low pressure chamber. The effects of
hypoxia on other peripheral stimuli have also been
studied (Kobrick 1972).
A special opportunity to study the CNS effects of
high altitude occurred during the India-China border war in the early 1960s when large numbers of
Indian troops were rapidly taken to an altitude of
4000 m and remained there for as long as 2 years.
Sharma and his colleagues (1975) measured psychomotor efficiency in 25 young Indians ranging in age
from 21 to 30 years. Psychomotor performance
including speed and accuracy was determined by
administering a hand-eye coordination test in which
a stylus was moved in a narrow groove so that it did
not touch the sides. The tests were performed at sea
level and at an altitude of 4000 m after periods of 1,
10, 13, 18 and 24 months. Figure 16.3 shows how
overall psychomotor efficiency declined over the first
10 months of altitude exposure but then recovered
somewhat over the ensuing 13 months as a result of
acclimatization.
Overall psychomotor efficiency as shown in Figure
16.3 includes both the speed and accuracy scores
from the test. Figure 16.4 shows a breakdown of the
accuracy and speed of this test of psychomotor performance. Note that the accuracy of the measurement
increased substantially after the 10-month period but
there was little improvement in speed. This result is
consistent with the impression given by many people
who have worked at high altitude: thought processes
are slowed, but accurate procedures can be carried
out if one concentrates hard enough.

Central nervous system function at high altitude 197

Figure 16.3 Psychomotor efficiency in young adults rapidly taken

Figure 16.4 Same data as in Figure 16.3 except that

to an altitude of 4000 m where they remained for 2 years.

psychomotor efficiency is broken down into accuracy and speed

Psychomotor efficiency was calculated using a hand-eye

of hand-eye coordination. Note that the accuracy of the

coordination test which included speed and accuracy. Note the

measurement (solid line) increased after 10 months but there was

deterioration in psychomotor efficiency over the first 10 months,

relatively little improvement in speed (dashed line). (From

which then gradually improved. (From Sharma et a I. 1975.)

Sharma et al. 1975.)

In a related study, Sharma and Malhotra (1976)

compared the performance of three groups of Indians
drawn from the Gurkha, Madras! and Rajput areas
after 10 months' stay at an altitude of 4000 m. There
were no differences in the scores for hand-eye coordination and social interaction at altitudes for the three
ethnic groups. However, the Gurkhas showed a better
toleration of altitude stress as evidenced by the effects
on concentration, anxiety and depression.
In a study of 20 male soldiers exposed to a simulated altitude of 4700 m for 5-7 h, the relationships
between symptoms and signs of AMS, mood and
psychometric performance were studied (ShukittHale et al. 1991). It was found that evidence of AMS
was best correlated with symptoms, then mood
changes and least with performance.
An unusual opportunity for studying the effects
of very high altitude on mental performance was
offered by the 1960-11 Silver Hut Expedition when
several normal subjects spent up to 3 months at an
altitude of 5800 m. Mental efficiency was tested by
asking the subjects to sort playing cards into bins
using specially designed equipment which recorded
events on magnetic tape (Gill et al 1964). It was
found that the efficiency of sorting cards was less
at the high altitude than at sea level. The ineffi-

ciency took the form of a delay in placing the

cards into the correct bins rather than errors of
sorting. Again these results reinforce the common
notion that accurate work can be done at high altitude, but it takes longer, and more effort in concentration is required. Cahoon (1972) also showed
a reduced efficiency of card sorting in eight normal
subjects exposed to a simulated altitude of 4600 m
for 48 h.
During the 1981 AMREE, a series of psychometric
tests was carried out prior to the expedition, at the
Base Camp (5400 m), at the Main Laboratory Camp
(6300 m) and immediately after and 1 year after the
expedition (Townes et al. 1984). The main emphasis
was on a comparison of CNS function before and
after exposure to extreme altitude, and only a few of
the measurements made at high altitude were
reported. However, finger-tapping speed decreased
significantly over the course of the expedition. Mean
taps of the right hand were 53.7 (pretest), 52.6
(5400 m altitude), 50.8 (6300 m altitude), 48.1 (on
subjects returning to 6300 m altitude from 8000 m)
and 45.4 (immediately after the expedition). It is not
clear from these results whether the reduction in
finger-tapping speed was a function of altitude, time
at high altitude, or both.

198 Central nervous system

16.43

Electroencephalogram

Ryn (1970, 1971) reported EEC abnormalities in 11

of 30 climbers who had been over 5500 m altitude.
The predominant abnormality was a decreased frequency of alpha waves and a diminution of their
amplitude. He also reported paroxysmal and focal
pathology in EEC records performed at high altitude.
Zhongyuan and his colleagues (1983) also
reported changes in the EEC at altitudes above
5000 m in members of a Chinese expedition to
Mount Everest. There was a reduced amplitude of
the alpha rhythm but in this instance there was an
increase in its frequency. The EEC changes were less
than those observed during acute hypoxia of the
same degree in a low pressure chamber before the
expedition. Apparently members of the expedition
who tolerated the acute hypoxia well tended to show
fewer EEC changes on the mountain itself.
Nevison carried out an extensive series of EEC
measurements during the Himalayan Scientific and
Mountaineering Expedition of 1960-1. Although the
results were not written up in the open literature, he
apparently found no abnormalities in subjects living
at 5800 m. Also the EEC appearances were not altered
by hyperventilation or 100 per cent oxygen breathing.

16.5
RESIDUAL CENTRAL NERVOUS
SYSTEM IMPAIRMENT FOLLOWING
RETURN FROM HIGH ALTITUDE
In view of the known vulnerability of the CNS to
hypoxia, it is hardly surprising that neurobehavioral
abnormalities can be demonstrated at high altitudes.
However, there has been great interest in the possibility of residual impairment of CNS function following return to sea level.
An extensive study was carried out by Townes et
al. (1984), referred to in section 16.4.2. The subjects
were 21 members of the 1981 AMREE, and all were
males between 25 and 52 years of age with a mean age
of 36.4 years. The general level of education was high,
with 15 subjects having either an MD or PhD degree.
Before the expedition, the following psychological
tests were administered at the San Diego Veterans
Administration Hospital: Halstead-Reitan battery
(Reitan and Davison 1974), repeatable cognitiveperceptual-motor battery (Lewis and Rennick 1979),

selective reminding test (Buschke 1973) and

Wechsler memory scale (Russell 1975). These same
measurements were repeated immediately after the
expedition in Kathmandu, Nepal. At an expedition
meeting held in Colorado 1 year later, the following
tests were readministered: Halstead-Wepman aphasia screening test, B trials and the finger-tapping test
from the Halstead-Reitan battery, the digit vigilance
task from the repeatable battery, and a verbal passage
from the Wechsler memory scale.
Table 16.1 shows the significant changes found
between pre-expedition, post-expedition and followup performance on the neuropsychological tests. It
can be seen that verbal learning and memory declined
significantly from the beginning to the end of the
expedition as measured by the Wechsler memory
scale. In the Halstead-Wepman aphasia screening test,
the number of expressive language errors increased
significantly between pre-test and post-test after the
expedition. The number of aphasic errors was significantly related to the altitude attained by the subject.
As indicated in section 16.4.2, finger-tapping
speed decreased significantly over the course of the
expedition. This was measured by requiring the subject to tap a lever as rapidly as possible over a period
of 10 s. For a test to be acceptable, five measurements
on each hand gave a difference of fewer than five taps
between trials. Before the expedition all subjects
reached this criterion. However, at Kathmandu
immediately after the expedition, 15 of 20 subjects
could not sustain motor speed, and 13 of 16 subjects
could not do so 1 year later.
These findings are of great interest because they
provide strong objective evidence for CNS deterioration as a result of exposure to high altitude, a subject
which has been debated vigorously in the past.
However, other authors have reported similar or
consistent findings. Ryn (1970,1971) also found persistent abnormalities in a group of 20 male and 10
female Polish climbers several weeks after a
Himalayan expedition. Half of the male climbers
who ascended over 5500 m experienced symptoms
similar to the acute organic brain syndrome, and for
several weeks after the expedition they had changes
in affect and impaired memory. Eleven of the 30
climbers had EEC abnormalities immediately after
the climb. Psychological testing (Bender, Benton and
Graham-Kendall tests) was reported to be normal in
13 subjects, borderline in 12 and indicative of
organic pathology in 5 climbers.

Residual central nervous system impairment following return from high altitude 199
Table 16.1 Wilcoxon signed-rank tests comparing performance before, immediately after (in Kathmandu), and 1 year
after an expedition to Mount Everest

Improved performance
Tactual performance test
(right hand)
Category test
Decline in performance
Finger-tapping test
Right hand
Left hand
Criterion right
Criterion left
Wechsler memory scale
Short-term verbal recall
Trials to criterion
Long-term verbal recall
Aphasia screening test

4.68 + 1.56

3.86 + 1.46

2.72*

24 .29 15.46

11.05 + 8.39

3.48+

53.71 4.07
47.65 4.60
1.00 + 0
1.00 + 0

45.40 + 6.18
42.45 + 5.96
0.14 + 0.36
0.14 + 0.36

48.40 + 6.60
41.73 + 5.23
0.27 + 0.46
0.13 0.35

3.39+
2.30*
3.06*
2.93*

1.32
0.66
0.73
0.54

2.20*
2.93*
2.67*
2.93*

18.12 1.90
1.24 + 0.44
16.35 2.91
0.59 + 0.79

15.90 + 2.15
2.40 + 1.54
12.70 + 3.78
1.25 + 1.25

17.13 + 2.20
2.27 0.70
14.50 2.85
0.47 + 0.52

2.60*
2.37*
2.32*
2.22*

2.12*
0
2.75
2.31*

0.98
2.67*
0.94
0.47

Source: Townes et al. (1984).

* p < 0.01;+ p < 0.001; */J < 0.05.

Persistent cognitive impairment was described in

five world-class climbers who had reached summits
over 8500 m without supplementary oxygen (Regard
et al. 1989). The abnormalities were in the ability to
concentrate, short-term memory, and cognitive flexibility (the ability to shift from one learned concept
to another).
In a brief report, Cavaletti et al. (1987) showed
residual impairment of memory in seven climbers
who returned to sea level after ascending to 7075 m
on Mount Satopanth in India without supplementary oxygen. The measurements were made before
leaving Italy, at the base camp after the ascent, and
75 days after the expedition. It was shown that memory performance decreased both at base camp and, to
a lesser degree, at sea level 75 days after the climb.
However, tests of fluency and 'idiomotor ability'
were unaffected by altitude. In a more recent study,
persistent changes in memory, reaction time and
concentration were reported 75 days after a single
ascent over 5000 m (Cavaletti and Tredici 1993).
One study reports cortical atrophy and brain magnetic resonance imaging (MRI) changes in 26
climbers who ascended to over 7000 m without supplementary oxygen (Garrido et al. 1993). No MRI

studies were performed before the climbs; the measurements were made 26 days to 36 months after
return to sea level. The controls were 21 normal subjects, and 46 per cent of the climbers showed MRI
abnormalities.
Not everyone has found CNS abnormalities following return after ascent to very high altitude. For
example, Clark et al. (1983) tested 22 mountaineers
before and 16-221 days after Himalayan climbs
above 5100 m with a battery of psychological and
neurophysiological tests but found no evidence of
cerebral dysfunction. This was a well designed study
and it is not clear why these climbers showed no
abnormalities. In another study, Anooshiravani et al.
(1999) carried out brain MRI studies and performed
neuropsychological testing on eight male climbers
before and after ascents to over 6000 m without oxygen. Although they found increases in symptoms of
AMS, there were no alterations in brain imaging or
neuropsychological tests between 5 and 10 days after
returning to sea level.
Measurements from the 1985 Operation Everest II
confirmed the changes in psychometric function
found on the 1981 AMREE, and extended the observations in an interesting and unexpected direction.

200 Central nervous system

During Operation Everest II, eight normal subjects

spent 40 days in a low pressure chamber and were
gradually decompressed, ultimately being exposed to
the simulated altitude of the Everest summit.
Impairments in motor speed and persistence, memory, and verbal expressive abilities were found after
the simulated ascent, just as with the 1981 Everest
expedition (Hornbein et al. 1989).
The new finding was a significant negative correlation between hypoxic ventilatory response and
neurobehavioral function measured after the expedition. In other words, those climbers with the largest
hypoxic ventilatory response showed the greatest
decrement in neurobehavioral function. This was
unexpected; indeed, the prediction might have been
that those who increased their ventilation most
would protect their CNS function by preserving their
alveolar and therefore arterial P0r
A hypothesis to explain these unexpected findings
was advanced by Hornbein et al. (1989). They argued
that the subjects with the highest hypoxic ventilatory
response would reduce their arterial PC02 the most
and therefore develop the most cerebral vasoconstriction. This in turn would cause the most severe
cerebral hypoxia even though their arterial P02 would
actually be higher than that in the subjects with the
smaller ventilatory responses to hypoxia.
Note that this hypothesis is not supported by the
measurements of cerebral blood flow against arterial
Pcc,2 in anesthetized dogs shown in Figure 16.2.
Those data show that cerebral blood flow apparently
levels off at values of Pcc,2 below approximately
15 mm Hg. However, the situation with acclimatization may be different because the arterial pH returns
towards normal and this may improve cerebral blood
flow. In addition, the scatter in the data is such that
this result may not be reliable. It should also be
pointed out that the relationship between cerebral
blood flow and arterial PC02 is very sensitive to the
systematic arterial pressure (Harper and Glass 1965).
Hypotensive dogs show a much smaller change in
cerebral blood flow for a given change in Pcc,2 than
normotensive animals. Whether changes in systemic
blood pressure occur at extreme altitudes is not
known, although there are no obvious alterations at
5800 m (Pugh 1964c).
The correlation between hypoxic ventilatory
response and residual impairment of CNS function
leads to an interesting paradox. On the one hand, a
brisk hypoxic ventilatory response is advantageous

for a climber to reach extreme altitudes because

otherwise the alveolar P02 cannot be maintained at
the required levels. However, the only way of maintaining the P02 is by extreme hyperventilation, which
reduces the arterial Pco2> which in turn reduces cerebral blood flow. Thus such a climber is likely to suffer more residual central nervous impairment. In
other words, the climber who is endowed by nature
to go the highest is likely to suffer the most severe
nervous system damage.

16.6
EFFECT OF OXYGEN ENRICHMENT
OF ROOM AIR ON NEUROPSYCHOLOGICAL
FUNCTION AT HIGH ALTITUDE
Increasing numbers of people are commuting to
high altitude for commercial purposes such as mining, and scientific purposes such as astronomy (see
Chapter 29). In order to reduce the neuropsychological impairment that occurs at high altitudes, oxygen
enrichment of room air is now being tested. This is
remarkably effective because every 1 per cent
increase in oxygen concentration (for example from
21 to 22 per cent) reduces the equivalent altitude by
about 300 m. Gerard etal. (2000) evaluated the effectiveness of enriching room air oxygen by 6 per cent at
simulated 5000 m altitude. A randomized doubleblind study was carried out on 24 subjects who
underwent neuropsychological testing in a specially
designed facility at 3800 m that could simulate both
an ambient 5000 m atmosphere and an atmosphere
of 6 per cent oxygen enrichment at 5000 m. The 2-h
test battery of 16 tasks assessed various aspects of
motor and cognitive performance. Compared with
simulated breathing air at 5000 m, oxygen enrichment resulted in higher arterial oxygen saturations,
quicker reaction times, improved hand-eye coordination, and a more positive sense of well being, each
significant at the p < 0.05 level.
It is interesting that other aspects of neuropsychological function were not significantly improved by
6 per cent additional oxygen. One reason maybe that
short-term concentration may temporarily overcome
real underlying deficits. The problem was succinctly
stated by Barcroft et al. (1923) reporting on the
1921-2 International High Altitude Expedition to
Cerro de Pasco, Peru (4330 m). Barcroft wrote:

Effect of oxygen enrichment of room air on neuropsychological function at high altitude 201
Judged by the ordinary standards of efficiency in
laboratory work, we were in an obviously lower category at Cerro than at the sea level. By a curious
paradox this was most apparent when it was being
least tested, for perhaps what we suffered from
chiefly was the difficulty of maintaining concentration. When we knew we were undergoing a test, our
concentration could by an effort be maintained
over the length of time taken for the test, but under
ordinary circumstances it would lapse. It is, perhaps, characteristic that, whilst each individual
mental test was done as rapidly at Cerro as at the
sea level, the performance of the series took nearly

twice as long for its accomplishment. Time was

wasted there in trivialities and 'bungling', which
would not take place at sea level (Barcroft et al.
1923).
In view of the above, it would be very interesting to
develop neuropsychological tests which were
embedded in the normal daily activities of the subject. In other words, it would be valuable to be able
to measure the mental efficiency of the subjects
when they were unaware of being tested. A formal
study along these lines has not yet been carried out
at high altitude.

17
High altitude populations
17.1 Introduction
17.2 Demographic aspects
17.3 Fetal and childhood development

203
203
204

SUMMARY
Many people live permanently at altitudes which
have a significant effect on their physiology (see
Chapter 3 for numbers and world distribution).
Studies of such populations are hampered by the
problem of appropriate comparison groups. Often a
group of high altitude residents is compared with a
group of lowlanders from a different ethnic, socioeconomic and genetic background so that it is difficult to know to what factors any differences may be
attributed. Also it is becoming clear that not all high
altitude residents are the same. Recent studies have
found interesting differences between South
American and central Asian high altitude residents.
Altitude residence does not seem to have important demographic effects; economic factors are of
greater importance. Fertility, which is reduced in
newcomers to altitude, seems to be normal in peoples resident for generations. Fetal growth in the last
stages of pregnancy is retarded and birth weight falls
with increasing altitude of residence. Growth in
childhood has been claimed to be retarded but continues for longer, though again this could be due, in
part at least, to economic or nutritional factors rather
than altitude per se.
The physiology of high altitude residents differs
from that of lowlanders at altitude in some respects.

17.4 Physiology
17.5 Adaptation to hypoxia over generations
17.6 Diseases

206
209
209

The former have lower total ventilation at rest and

exercise and blunted hypoxic ventilatory response
(though in Tibetans this is less so than in South
American highlanders). Despite lower ventilation
their oxygen saturation and P02 are similar to those
of lowlanders at altitude. They have higher lung diffusing capacities than lowlanders, an important
advantage at altitude where work rate is limited by
diffusion. They have slightly larger lungs. Animals
adapted to high altitude have very little pulmonary
artery pressor response to hypoxia. Tibetans show a
degree of this adaptation, but not South American
high altitude residents. There are also differences in
hemoglobin concentration and oxygen saturation
between these populations, all suggesting that the
Tibetans, with their longer lineage at altitude, have
undergone a greater degree of altitude adaptation.
Certain diseases are found commonly among altitude residents. Again some are the result of socioeconomic factors and are common in poor
populations at sea level. Cold and cold injury are
more common at altitude but, of course, not confined to it. The commonest disease due to altitude
hypoxia is chronic mountain sickness. This is covered in Chapter 21. Others include chemodectoma, a
benign tumor of the carotid body, and a high incidence of patent ductus arteriosus in infants. Goiter,
though strictly not confined to high altitude, is much

Demographic aspects 203

more prevalent there since iodine-deficient soils are

more common at high elevations and possibly the
demands for iodine are greater at altitude. Finally
sickle cell disease, though not caused by altitude, is
more serious there.

17.1

INTRODUCTION

This chapter considers the characteristics of people

born and raised at high altitude and whose ancestors
have resided at high altitude for many generations. In
Chapter 3 the locations of these populations have
been discussed. In general the altitude considered is
above 3000 m. The duration of residence of the population is impossible to determine; it ranges from
perhaps 50000 to 100000 years in Tibet and
20 000-30 000 years in the Andes to a few generations in the high mining towns of Colorado, USA.
Our knowledge of the effect of lifelong residence at
altitude has come from studies of particular peoples.
A major problem in interpreting results is to decide
whether the characteristics found to differ from lowland populations are really due to the high altitude
environment (hypoxia or cold) or due to racial,
nutritional or economic factors.
Some studies have sought to eliminate racial factors by using low altitude residents of the same ethnic
background as controls. It is difficult to control for
nutritional factors since high altitude residents may
well be economically disadvantaged when compared
with their low altitude controls. This seems to be the
case in the Andes. The effects of poor nutrition and
chronic hypoxia are similar on factors such as growth
and development, thus confounding the interpretation of results. The economic advantage may be
reversed, as in Ethiopia, where the highland regions
are free from malaria and the residents more wealthy
and better fed. The result is that studies from this
part of the world do not show the differences
between high and low altitude residents that are
reported from the Andes. There are fewer studies
from the Himalayas and Tibet than from the Andes,
though this has been redressed in recent years with a
number of studies from Lhasa.
However, if these reservations are kept in mind,
some conclusions can be drawn from the many surveys about the effects of lifelong residence at high
altitude, especially on birth weight and childhood

development. Recent studies have addressed the

question of differences between South American and
Tibetan high altitude residents and the related one of
whether there has been natural selection for giving a
biological advantage to either of these populations.

17.2

DEMOGRAPHIC ASPECTS

17.2.1 Population age and sex

distribution
A few high altitude groups have been analyzed in
some detail and the population of the Nunoa district
(4000 m) of Peru showed some differences compared
with the total Peruvian population (Baker and Dutt
1972). The high altitude population was somewhat
younger and the ratio of females to males was larger
during infancy and childhood, but in addition there
appeared to be more elderly people among the high
altitude than the general population.
The explanation seems to be that, in the high altitude population, there was a high birth rate and high
adult emigration rate. Male mortality was higher
than female in infancy, childhood and early adolescence. The larger number of older individuals may
have been due to the prestige associated with telling
observers that they were of a great age. Claims to
longevity are hard to substantiate because birth certificates and baptismal registers are seldom kept and
some individuals lie outrageously about their age. In
north Bhutan the oldest individuals were over 80 but
not above 90 years old (Jackson et al. 1966, p. 99) and
some Tibetan lamas claim to have lived to a great age.
There seems to be little concrete evidence for
unusual longevity at high altitude.
In the Khumbu region of northeastern Nepal,
male infant mortality was higher than female. There
was little permanent emigration but a higher percentage of males was involved in accidents. In northwest Nepal the number of males born relative to
females was higher but mortality in male infants was
increased (Baker 1978).

17.2.2

Fertility

Adaptation to the environment must include the

ability of the species to reproduce. The Spanish who
occupied the high altitude regions of South America

204 High altitude populations

in the sixteenth and seventeenth centuries found

that neither their animals nor their womenfolk had
live offspring. This was in contrast to the indigenous animals and peoples. Clegg (1978) quotes two
well-observed Spanish accounts of La Calancha
(1639) and Cobo (1653). The former recounts the
early history of the city of Potosi (4060 m) in present day Bolivia with a population of 20000
Spaniards and 100000 Indians. Children born to
Spanish couples died either at birth or within
2 weeks. Pregnant Spanish women developed the
habit of going down to low altitude for their pregnancy and delivery and keeping their babies there
until a year old. Han Chinese women living in Tibet
follow a similar pattern. The cause of failure to
thrive in these infants may well have been subacute
mountain sickness (Chapter 21). The Amerindians,
of course, had no such problems nor do the
indigenous Tibetans. It was not until 53 years after
its foundation that the first Spanish child was born
and reared in the city. Cobo says that Jauja
(3500 m), the early capital of Peru, was considered
'a sterile place' where horses, pigs, or fowls could
not be raised, whereas 100 years later it was a principal area producing pigs and poultry and supplying
Lima with these products.
Cobo also pointed out that infant survival
depended upon the proportion of Indian blood in the
child, with pure-blooded Spanish children mostly
dying, children of mixed blood faring rather better,
and pure-blooded Indian children having the lowest
mortality, despite much poorer living conditions.
What is the cause of this lack of fertility in lowlanders at altitude? Sperm counts in lowland men fall
temporarily on going to altitude but then recover.
Testosterone levels also fall and then recover after a
week or two (section 15.9.4). In the female, on going
to altitude, there may be temporary disturbances in
menstruation (Sobrevilla et al. 1967). Conception
rates are virtually impossible to measure, especially
since chronic hypoxia may increase the frequency of
early abortions. The reduced fertility may be due to a
number of factors, possibly reduced conception,
probably increased numbers of early abortions, stillbirths and neonatal deaths.
In altitude residents fertility was thought to be
reduced. Hoff and Abelson (1976), using aggregate
data from Peru, found that fertility, measured as the
number of children under the age of 5 divided by the
number of women aged 15-49 years, fell linearly with

altitude (p < 0.01) but they were cautious when interpreting the data on which this was based. They also
found that high altitude women who migrate to low
altitude increase their fertility. However, more recently
both Carrillo (1996) and Gonzales etal. (1996) found
global fecundity rates higher than at sea level.

173
FETAL AND CHILDHOOD
DEVELOPMENT
17.3.1 Pregnancy

ABORTION
Abortion rates are notoriously difficult to measure,
but Clegg (1978) quotes a number of Andean studies
giving incredibly low rates ranging from 0 to
1 per cent (compared with worldwide rates of about
15 per cent). He suggested this might be due to a high
rate of very early abortions (before 2 weeks) which
would be unrecognized and would help to account
for the low fertility. In Ethiopian women, Harrison et
al. (1969) reported a rather higher rate (9.1 per cent)
at 3000 m compared with less than 1 per cent in an
ethnically similar population at low altitude; however, both rates are low compared with rates in many
populations.
PLACENTAL GROWTH

Placentas are not significantly heavier at high altitude

but since birth weights are low the placental/birth
weight ratio is significantly increased (McClung
1969, Mayhew 1986), clearly an adaptation which
would benefit fetal oxygenation. The numbers of villi
and capillaries are increased in the placentas from
high altitude women; this increases the surface area
for diffusion (Clegg 1978), although Mayhew (1986)
found a smaller surface area of villi but a thinner diffusion barrier, thus preserving the membrane diffusing capacity. Placental infarcts are more common in
altitude placentas and more frequent in women with
a European admixture of genes (McClung 1969).
FETAL GROWTH

The evidence suggests that, after the hazards of the

first few weeks of pregnancy, growth is probably
normal until the last trimester, when it slows to produce a lighter baby at term. The cause of this growth

Fetal and childhood development 205

retardation is not clear, since the evidence reviewed

by Clegg (1978) suggests that the fetus at this altitude
is not hypoxic compared with lowland fetuses.
Possibly this is a genetic adaptive change with elimination, over generations, of genes which produce a
larger baby. This would be advantageous since
smaller babies are less likely to outgrow the placental
capacity for oxygen transfer.

173.2
Birth weight and infant
mortality
Results from a number of studies in the Andes and
Tibet showed lower birth weight at altitude (Haas
1976, Li 1985). The mean weight declined from
about 3.5 kg in Lima to 2.8 kg at Cerro de Pasco
(4300 m) and, although there is the possibility that
the nutritional status of mothers maybe a factor, it is
unlikely to account for more than a proportion of
this difference. A similar effect of altitude has been
reported from the USA (Lichty et al. 1957, Grahn and
Kratchman 1963, linger et al. 1988). Women native
to high altitude who descend to low altitude have
heavier babies at low altitude (Hoff and Abelson
1976). These studies include women from both
indigenous high altitude populations and low altitude stock, and indicate that it is the high altitude
environment rather than genetics which result in low
birth weights. A recent study from Colorado also
concludes that altitude is an independent factor in
causing low birth weights. The authors obtained data
from 3836 birth certificates and found that none of
the characteristics associated with low birth weight gestational age, maternal weight gain, parity, smoking, hypertension, etc. - interacted with the effect of
altitude; the decline in birth weight averaged 102 g
per 1000 m (Jensen and Moore 1997). However,
genetic factors may play a role. In a study in Lhasa
(3658 m) Niermeyer et al. (1995) reported that Han
Chinese infants had lower birth weights than Tibetan
babies born at the same altitude. They also had lower
Sa02 and higher hemoglobin levels. Possibly the
genetic factors work through giving better oxygenation to Tibetan mothers (see section 17.5.2).
Infant mortality depends heavily on living standards and medical facilities and the very high infant
mortality rates reported probably reflect these factors more than the effect of altitude per se. In
Ethiopia, Harrison et al. (1969) reported a rate of

200 per 1000 live births at high altitude and 176 per
1000 at low altitude, whereas in the Andes a rate of
180 per 1000 was found in the rural area of Nunoa
(4000 m) but only 73 per 1000 in urban La Paz
(Baker 1978). In Himalayan Sherpas, Lang and
Lang (1971) gave a figure of 51 per 1000 at 4300 m,
and in North Bhutan the rate was 189 per 1000
(Jackson et al. 1966, p. 99). In experimental animals
under controlled conditions, hypoxia increases
neonatal mortality, so probably the high rates
found in mountain peoples are at least partly due to
the altitude. Apart from the direct effect of hypoxia
an important indirect effect may be through the
reduced amount of liver glycogen present at birth,
an important energy store until suckling becomes
established (Clegg 1978).

1733

Growth through childhood

The high altitude baby starts life smaller than the

average low altitude baby does, and its early growth is
slower. Milestones such as sitting and walking are
slightly later but the differences between high and
low altitude residents of the same race are less than
those between different races or between urban and
rural populations (Clegg 1978).
In Quechua Indians in Peru, throughout childhood the high altitude child lags behind his low altitude counterpart in height by about 2 years. The
adolescent growth spurt is less pronounced in high
altitude youths but their growth continues for about
2 years longer and their adult stature is not reached
until 22 years of age (Frisancho 1978). In Ethiopia,
there were no such differences. Indeed, high altitude
males were taller and heavier for their age than lowlanders. In the Himalayas, a comparison of high
altitude Sherpas (3075-5050 m) with Tibetans resident at 1400 m was made by Pawson (quoted by
Frisancho 1978) who found no difference in the
height of children in these populations, though
other indices of maturation (skeletal and dental
development and menarche) show the Sherpa children to lag behind the low altitude Tibetans.
Recently a study from Ecuador found very little difference in rates of body weight increase in children
at altitude compared with children from low altitude. There were some minor differences in rates of
height increase but the authors conclude that
hypoxia plays a relatively small role in shaping

206 High altitude populations

growth in the first 5 years after birth (Leonard et al.

1995).
On the other hand, investigations amongst the
children of Kirghiz tribes of the Tien Shan mountains showed delayed growth in the high altitude
children, equivalent to a lag of about 1 year. The altitude of residence was 2300-2800 m but in the summer months they go up to 3500 m to graze their cattle
(Frisancho 1978).
Menarche is a milestone well documented in studies from various high altitude regions and, in girls
living in the Andes, Himalayas and Tien Shan, it is
1-2 years later than in low altitude girls (Frisancho
1978, Jackson et al. 1966, pp. 40-4). The Ethiopian
highlanders again are the exception as no difference
was found (Harrison et al. 1969). Adrenarche, the
increase in serum androgens, also occurs 1-2 years
later in children at altitude compared with sea level
in Peru (Gonez etal. 1993).

17.4

PHYSIOLOGY

17.4.1 Stature, lung development and

function
Compared with Europeans and North Americans,
most high altitude residents have a smaller stature
and are lighter in weight, but when compared with
people of similar race and living standards most of
this difference disappears. The delayed growth (see
above) is almost counteracted by the prolongation of
active growth to beyond 20 years.
One of the most quoted aspects of lifelong adaptation to high altitude is the deep-chested development
of the thorax in high altitude residents (Barcroft
1925). This has been documented by measurement
of chest circumference and vital capacity in South
American Indians living above 4500 m but is quite a
small difference even in this population. Vital capacity was about 300 mL higher than predicted when
corrected for body size (Velasquez 1976). However,
at 3500 m these measurements were smaller and less
than the values published in the USA. High altitude
residents in the Himalayas do not have large circumference chests or bigger vital capacities than lowlanders (Frisancho 1978) nor do younger white
residents of Leadville (3100 m), but those over
50 years of age did have significantly larger vital

capacities, by 440 mL, than predicted (DeGraff et al.

1970). Sun etal. (1990) compared Tibetans and Han
Chinese residents of Lhasa. Their mean ages, heights
and weights were similar, but, whereas the Tibetans
were lifelong residents, the Han have been resident
for a mean time of 8 years. The Tibetans had vital
capacities significantly greater than the Han did:
5080 mL compared with 4280 mL.
In Andean residents at 4540 m, the total lung
capacity is about 500 mL larger than at sea level, most
of the increase being due to increased residual volume (Velasquez 1976). Infants born at high altitude
have greater thoracic compliance than infants of the
same ethnic background born at low altitude
(Mortola et al. 1990). In adults the thoracic blood
volume is increased and the residual volume/total
lung capacity ratio increases from 21 per cent to
28 per cent in high altitude compared with low altitude residents. There may be some benefit from this
since it would have the effect of reducing the breathby-breath oscillations of Pcc,2 and, hence, pH. At altitude these oscillations would otherwise be increased
due to the reduction in plasma bicarbonate as part of
the acclimatization process (Chapter 5). However,
these changes in lung volumes, even when found, are
quite small and probably have little effect on performance.
The increased lung capacity may allow for an
increased area for gas diffusion which, together with
the increased blood volume, results in increased lung
diffusing capacity. Details of studies in Andean and
Caucasian residents are given in section 6.4.2. This
increase in gas transfer should give the altitude resident a distinct performance advantage over the newcomer to altitude. Recent work from Tibet by Chen
et al. (1997) indicates that Tibetan highlanders also
have higher lung diffusing capacities when compared
with Han Chinese. Also Samaja et al. (1997), who
studied Sherpas and Caucasian lowlanders at 3400
and 6450 m, found that the Sherpas were less alkalotic at the higher altitude due to a higher -PCo2>
although the P02 and 5a02 were the same as those of
Caucasians. This indicates that their oxygen transport was more efficient.
Vital capacity decreases with age at sea level but
this reduction is much greater at altitude, at least
in Andean residents (Monge et al. 1990), which
may account in part for the increasing incidence
of chronic mountain sickness with age (Chapter
21).

Physiology 207

17.4.2 Yentilatory control at rest and

exercise
Newcomers to high altitude find, often to their surprise, that they have to hyperventilate on the slightest
exertion. They may notice that high altitude residents seem to be relatively unaffected in this way.
Measurements of resting and exercise ventilation
in high altitude residents confirmed this impression
to be true. Chiodi (1957) showed that resting ventilation was higher in newcomers to altitude than in residents. At 3990 m the values were 5.3 and 4.5 L
mhr1 m2, and at 4515 m, 5.6 and 4.9 L mhr1 m2 for
newcomers and residents respectively. The Pacc,2 values were in accordance with these differences.
Santolaya et al. (1989) studied workers at the
Aucanquilcha mine (5950 m) in Chile. Their mean
Pac02 was 27.5 mmHg whereas lowlanders at that
altitude would have a value about 5 mm Hg lower,
indicating ventilation 22 per cent higher. They also
showed no respiratory alkalosis (pH 7.4), which lowlanders would have at that altitude.
On exercise, Buskirk (1978) found a similar distinction in Andean high altitude residents as did
Lahiri et al. (1967) in Sherpa subjects compared with
lowlanders at altitude. It is likely that this lower ventilation in high altitude residents is due to their low
hypoxic ventilatory response (HVR), which is well
documented (Chapter 5), since HVR correlates with
exercise hyperventilation. As discussed in Chapter 5
this blunting of the HVR appears to take place over
decades at altitude. Children resident at high altitude
have normal HVR and this blunting is seen in white
subjects resident in Leadville (3100 m) in Colorado,
so it does not seem to be genetically determined
(Weilefa/. 1971, Lahiri et al. 1976).
Work by Zhuang et al. (1993) showed some interesting differences between lowland born Han
Chinese and highland born Tibetans studied in
Lhasa (3658 m). The Han had migrated to altitude
in childhood, adolescence or adulthood. They
showed the decline in HVR with length of residence
at altitude as seen in Colorado altitude residents,
but the Tibetans, who had a higher HVR (parameter
A) than the Han, showed very little decline with age.
However, Tibetans showed a paradoxical increase in
ventilation on breathing 70 per cent oxygen, a
response not seen in Han subjects. Tibetan lifelong
residents at 4400 m when studied at 3658 m and
compared with Tibetans living there had blunted

HVRs though their resting ventilation was similar

(Curran et al. 1995). Recently the same team has
looked at a group of men of mixed Han-Tibetan
parentage. They found that HVR was decreased with
time of residence at altitude but that resting ventilation did not reduce, as is the case with Han subjects.
They exhibited the same paradoxical response to
oxygen breathing as did Tibetan subjects (Curran et
al. 1997).
Beall and colleagues have compared Tibetan and
South American Aymara highlanders. They found
resting ventilation was roughly 1.5 times higher in
the Tibetans and HVR about double that of the
Aymara. They also found that the contribution of
genetic differences to the variance in ventilation was
35 per cent in the Tibetan population and nil in the
Amayra. The figures for HVR were 31 and
21 per cent respectively (Beall et al. 1997a; see also
section 17.5.2).

17.43

Hemoglobin concentration

The increase in hemoglobin concentration at altitude

is one of the best known adaptations to altitude
hypoxia. It is found in both acclimatized lowlanders
and lifelong residents at altitude. This is discussed in
detail in Chapter 8.
In the Andes, some workers have found very high
hemoglobin concentration in residents (Talbott and
Dill 1936, Dill et al. 1937, Merino 1950) and suggested that this is part of their long-term adaptation
to altitude. However, subjects may have been
included in these study populations who would now
be considered to have chronic mountain sickness or
Monge's disease (Chapter 21). More recent studies
have not found such high levels or a significant difference between residents and acclimatized lowlanders (Penaloza etal. 1971). Frisancho (1988) reviewed
the published data and showed that hemoglobin
concentration values from mining areas in the Andes
were higher than from nonmining areas, and that if
studies from nonmining areas were compared with
those from the Himalayas there was no significant
difference. However, Beall et al. (1998) found
Aymara Andean high altitude natives to have
hemoglobin concentration significantly higher, by
3-4 g/dL, than Tibetans at a similar altitude.
In the Himalayas and on the Tibetan plateau,
residents tend to have rather lower hemoglobin

208 High altitude populations

concentration than acclimatized lowlanders. As discussed in Chapter 8, it is thought that, although a

modest rise in hemoglobin concentration (to perhaps 18.0 g/dL) is advantageous, values much above
this level are probably detrimental. So the Tibetans'
lower hemoglobin concentration values are considered to be evidence of greater altitude adaptation.
17'AA
The carotid body and
chemodectoma
Chronic hypoxia causes an increase in the size and
weight of the carotid body. This was first reported in
high altitude Andean natives by Arias-Stella (1969).
He found the weight of the two carotid bodies in residents of Lima to be just over 20 mg, whereas in altitude residents they totaled over 60 mg. Heath and
co-workers found a similar increased weight of
carotid bodies in patients with chronic hypoxic lung
disease. They found a good correlation between
carotid body and right ventricular weight, suggesting
that a common correlation with hypoxia was the
cause of the hyperplasia (Heath 1986).
The principal cell involved in this hyperplasia is
the sustentacular (type II) cell with compression and
obliteration of clusters of chief (type I) cells. This
type of hyperplasia is similar to that seen in systemic
hypertension (Heath 1986).
Chemodectoma, a tumor of the carotid body, is
rare at sea level, but appears to be relatively common
at high altitude. In 1973 Saldana et al. reported its
occurrence in a higher proportion of Peruvian adults
born and living at 4350 m than in those living at
3000m. All were benign and the incidence was
higher in women. An association between chemodectoma and thyroid carcinoma has been noted in
two patients at 2380 m (Saldana etal. 1973). No cases
of chemodectoma have yet been reported from the
Tibetan plateau or the high Himalayan valleys.
17.4*5

Cardiovascular adaptations

Andean high altitude residents share with newcomers the raised pulmonary artery and right ventricular
pressure due to the hypoxic pulmonary pressor
response (Chapter 7), resulting in right ventricular
hypertrophy (Recavarren and Arias-Stella 1964).
Indeed, in Andean children at high altitude, the usual
involution of the muscular coat of the pulmonary

artery after birth does not take place, or does so only

partially, so that the pulmonary arteries, both large
and small, show far greater muscularization than is
normal in sea level residents (Saldana and AriasStella 1963a,b,c).
This finding of right ventricular hypertrophy, continued muscularization of the pulmonary arteries
and raised pulmonary artery pressure in residents at
high altitude should be regarded as a response to
high altitude rather than an adaptation, since there is
no evidence that it has any physiological benefit.
Indeed, it merely throws more strain on the right
heart.
The purpose of the hypoxic pressor response in
humans at sea level, apart from its vital role in prenatal life, is presumably to redistribute blood away
from areas of the lung that are hypoxic because of,
for instance, atelectasis, and thus improve
matching of ventilation and blood flow in various
clinical situations. It would probably be beneficial
to lose this response at altitude, and the altitude
adapted yak would seem to have done this (section
17.5).
Studies in Tibetan highlanders suggest that they
have achieved a similar adaptation to the yak and do
not have raised pulmonary artery pressures at altitude and little rise on exercise (Groves et al. 1993)
though the numbers studied were small. Neither do
they develop the structural changes in their pulmonary arterial tree that are found in Andean highlanders (Gupta et al. 1992). The incidence of right
ventricular hypertrophic signs in the electrocardiograph (EGG) was found to be only 17 per cent in
Tibetans and 29 per cent in Han Chinese at the same
altitude (Halperin etal 1998).
Lifelong residents also have an increase in the
number of branches to the main trunks of their coronary arteries (Arias-Stella and Topilsky 1971).
Another adaptation of high altitude residents is
that, on exercise at altitude, their maximum heart
rate does not seem to be limited, as is the case for
acclimatized lowlanders. This is discussed more fully
in Chapter 7 and in relation to the adrenergic system
in Chapter 15. A recent study by Passino etal. (1996)
looked at the spectral analysis of ECGs of high altitude residents compared with lowlanders at altitude.
The high altitude residents did not show the reduced
vagal tone seen in lowlanders, which may indicate
the mechanism which allows this higher maximum
heart rate in highlanders.

Diseases 209

17.4.6

Adaptation to cold

Cold is a feature of life at high altitude (section

3.8.1). Further aspects of cold adaptation are considered in Chapter 24.

17.5 ADAPTATION TO HYPOXIA OVER

GENERATIONS
Most of the adaptations to hypoxia that have been
shown in humans appear to develop during a lifetime
of exposure. Even the blunting of the hypoxic ventilatory response has been shown to develop in people
of lowland stock over a period of decades (Weil et al.
1971). The lower hemoglobin concentration in
Sherpa and Tibetan subjects has been suggested as an
example of adaptation over many generations in
Tibetan stock.
17.5.1 The hypoxic pulmonary pressor
response
In animals, Harris (1986) has shown elegantly that in
cattle the pulmonary pressor response, or lack of it, is
genetically determined. The yak has little or no
response, whereas the cow has a brisk response. The
crossbred dzo has the blunted response of its yak parent, but the second cross of dzo and bull produces
50 per cent brisk and 50 per cent low response offspring. That is, the gene responsible for a low
response is dominant and the characteristic is inherited in a Mendelian way. Presumably, a low response
is an advantage at altitude, a brisk response being a
risk factor for brisket disease (named after the
brisket, the loose skin at the animal's throat). Thus,
we have a true adaptation achieved presumably by
environmental pressure selecting for the low
response gene. Similar adaptation has been found in
the llama.
There is evidence that in populations of Tibetan
origin a similar adaptation may have taken place.
Jackson (1968) found little EGG evidence of pulmonary hypertension in Bhutanese and Sherpa subjects at altitude, in that their mean frontal QRS axis
differed by only 10 from healthy Edinburgh adults,
in contrast to both lowlanders and Andean residents
at altitude, who have marked right axis deviation due
to pulmonary hypertension (Chapter 7). Groves et al.

(1993) found pulmonary artery pressures and resistance in five Tibetan subjects in Lhasa (3658 m) to be
within normal sea level values at rest and exercise. If
confirmed, this would mark out the Tibetan population as showing genuine altitude adaptation, presumably by natural selection over very many
generations.
17.5.2

Arterial oxygen saturation

In 1994 Beall and her colleagues reported that the

level of Sa02 was influenced by a single gene in a population of Tibetan women they had studied at
4850-5450 m (Beall et al. 1994). They later studied
another Tibetan population in the Lhasa region
(3800-4065m) and calculated that this gene
accounted for 21 per cent of the variance in 5a0z
(Beall et al. 1997b). More recently the same group
compared Tibetan with South American Aymara
women. They found that the Tibetans had 5a02 on
average 2.6 per cent higher than the Aymara, and also
that whereas much of the variance of Sa02 in the
Tibetan women could be attributed to genetic factors, no significant proportion of the variance could
be so attributed in the South American population
(Beall et al. 1999). Therefore there is the potential for
natural selection towards higher 5a02 in the Tibetan
but not in the Aymara population.

17.6

DISEASES

It is clear from the biography of Yu-Thog the elder

(786-911 CE), the physician-saint and founder of traditional Tibetan medicine, that a number of medical
conditions were known at high altitude from the earliest times. These included lung disease, leprosy,
venereal disease, a 'swelling of the throat' (possibly
diphtheria) and rabies, as well as urinary retention
and stones in the urinary tract (Rinpoche 1973,
p. 72).
Travelers to Lhasa in the eighteenth and nineteenth centuries, such as Hue and Gabet (Pelliot
1928, vol. 2 p. 250), reported epidemics of smallpox
and in 1925 it was estimated that 7000 people died in
and around Lhasa from this cause. Because of the
prevalence of smallpox in Tibet, in the eighteenth
century the Chinese placed a tablet in Lhasa giving
instructions on how to curb the disease, and it was

210 High altitude populations

also reported in south Tibet and Bhutan by Saunders

(1789) and in the Pamir (Forsyth 1875). The Tibetan
cure for smallpox was the skin of the ox and rhinoceros (Rinpoche 1973, p. 72), though a form of inoculation was used, apparently borrowed from China
and India (Das 1902). A kind of snuff prepared from
the dried pustules of smallpox patients was inhaled,
which induced a mild form of the disease, protecting
the snuff taker from the severe form as described by
the Pandit A-K (Walker, 1885). These conditions
(smallpox, rabies, leprosy, etc.) are not, of course,
caused by altitude.
Gallstones, commonly perceived as a disease of the
developed world, is also a common problem in high
altitude populations. Commoner in women than
men, increased alcohol consumption is associated
with a lower risk (Moro et al. 1999).
17.6.1

Birth defects

Apart from congenital heart disease, considered in

the next section, a high frequency of other birth
defects has been noted by Castilla et al. (1999). In a
collaborative study from three hospitals situated
between 2600 and 3600 m in Bogota (Columbia) La
Paz (Bolivia) and Quito (Ecuador) they found a high
frequency of craniofacial defects, cleft lip, microtia,
pre-auricular tag, brachial arch complex, constriction band complex and anal atresia; there was a low
frequency of neural tube defects, anencephaly and
spina bifida. The incidence of patent ductus arteriosus was not addressed.

17.6.2

Cardiovascular disease

CONGENITAL HEART DISEASE

Congenital cardiovascular malformations are common at altitude, with patent ductus arteriosus being
15 times commoner at Cerro de Pasco (4200 m) than
at sea level in Lima (Penaloza et al. 1964).
Marticorena et al. (1959) reported an incidence of
0.72 per cent of patent ductus arteriosus in children
born around 4300 m, compared with an incidence of
0.8 per cent for all congenital heart disease at sea
level.
In Xizang (Tibet), among the resident Tibetan
population the incidence of congenital heart disease
has been shown to range from 0.51 per cent to

2.25 per cent, with patent ductus arteriosus being the

most frequently encountered abnormality (Sun
1985). The greater the altitude the higher the prevalence; the highest documented incidence (2.5
per cent) occurred in Chinese emigrants (Zhang
1985). Presumably the cause of these high rates is the
lack of a sudden increase in oxygen levels in the few
hours after birth which normally triggers the reduction in pulmonary vascular resistance and the closure
of the ductus.
ATHEROSCLEROSIS

Studies of populations in the Andes suggest that both

coronary artery disease and myocardial infarction
are uncommon amongst high altitude residents. No
cases were found in one series of 300 necropsies carried out at 4300 m, and epidemiological studies in
South America have shown that both angina of effort
and EGG evidence of myocardial ischemia are less at
altitude than at sea level (Ramos et al. 1967). In the
Tibetan ethnic population of North Bhutan no
autopsy studies were available but angina seemed
uncommon, and, as judged by EGG recordings, evidence of coronary artery disease was minimal.
Studies from the Tien Shan and Pamir also suggest
that degenerative cardiovascular disease is rare in
these regions (Mirrakhimov 1978).
In autopsy studies of 385 Tibetan adults living in
the Lhasa area, arteriosclerosis of the aorta and its
main branches occurred in 81.8 per cent and of the
coronary artery in 65.5 per cent. In Qinghai, coronary artery disease was common and autopsies on
Tibetans showed the same incidence as in lowlanders, but the incidence of coronary infarction was low
(Sun 1985). Serum cholesterol levels were low in
Andean natives and in the Bhutanese high altitude
group studied; in the latter there was no progressive
increase with age (Jackson etal. 1966, p. 96).
HYPERTENSION

Hypertension is uncommon in high altitude populations in South America. In a study of 300 high altitude natives in Peru no significant rise in either
systolic or diastolic pressure occurred with age. Of
individuals aged between 60 and 80 years in the same
area, few had a systolic pressure above 165 mm Hg or
a diastolic pressure above 95 mmHg (Baker 1978).
There was no significant hypertension in ethnic
Tibetan populations of North Bhutan, and, of 70

Diseases 211
individuals examined, levels of blood pressure
above 165/90 mmHg were found in 4 per cent.
Hypertension was not found in a Sherpa population
studied in Northeast Nepal nor in populations studied in the Tien Shan or Pamir. In an Ethiopian group,
a slightly higher systolic pressure was found in males.
By contrast, Sun reports (1985, 1986) a relatively
high incidence of hypertension among indigenous
Tibetans. He also found an age-associated increase in
blood pressure. There was no tendency for hypertension to decline at higher altitudes and the blood
pressure was higher in women than in men. The incidence was greater in the urban population around
Lhasa than in rural populations. Similar observations
have been made in Tibetans living in high altitude
areas of western Szechuan. However, Han (Chinese)
immigrants to Tibet showed a lower incidence of
hypertension than did the Tibetans. In Qinghai
province (which contains the northeastern part of
the Tibetan plateau) the incidence of hypertension
appears to be lower than in Xizang.
The incidence of hypertension and lack of rise in
blood pressure with age in the South American and
Himalayan populations studied may be the product
of diet and behavior associated with a traditional
lifestyle. The cause of hypertension among Tibetans
is not clear. On the plateau, obesity is uncommon
and traditionally few smoke (though this is changing). However, they do have a very high intake of salt,
estimated at up to 1 kg per month, much of it taken
in their tea. They also add yak butter, which is often
slightly rancid. In the Bhutanese and Sherpa varieties
of 'Tibetan' tea neither the salt nor the butter content appears, by taste, to be as high. In all houses and
nomad dwellings there is a continuous supply of this
tea, which is offered to every visitor. Even when they
have migrated to low levels, Tibetans still drink large
quantities of it and may become very obese. The high
salt and butter intake may be a factor in the high incidence of hypertension in Tibetans.
However, a 15-year survey of Tibetan native highlanders living on the Tibetan plateau showed a low
incidence of systemic hypertension. A total of 7797
men and 8029 women were studied. Just over
2 per cent of this group had hypertension compared
with over 4 per cent of Chinese immigrants to Tibet.
The intake of salt varied. Tibetans in Zadou county
(4068 m) had the highest intake with an average of
14.6 g per day and an incidence of hypertension of
3.48 per cent. In Zhidou county (4179 m) the average

salt intake was 2.2 g per day and hypertension was

found in 2.62 per cent (Wu 1994a). By contrast, in
lowland Chinese the incidence of hypertension is
7.9 per cent (Liu 1986).

17*63

Infection

Direct exposure to increased solar radiation inhibits

the growth of some bacteria because of the ultraviolet
component of sunlight. Staphylococcus aureus is
greatly inhibited, but Escherichia coli is more resistant (Nusshag 1954). The number of bacteria in
ambient air decreases with altitude, and a study on
the Jungfraujoch (3400 m) in Switzerland showed
that, despite a large number of tourists, few bacteria
were present in the air.
High altitudes do not influence human bacterial
flora per se. However, a lower incidence of many
common infections of bacterial, viral and protozoal
origin was observed in soldiers at altitudes up to
5538 m (Singh et al. 1977). Examination of nasal
swabs in a high altitude population in North Bhutan
showed that there was only a 4 per cent carrier rate of
coagulase positive staphylococci; normally the incidence is between 29 and 40 per cent in western communities. A high frequency of p-hemolytic
streptococci, highly sensitive to penicillin, was found
in throat cultures, whereas in western communities
sensitivity to penicillin would be minimal (Selkon
and Gould 1966).
In the highlanders of Peru, Colombia and Ecuador,
oroya fever is found, which is caused by Bacillus bacilliformis becoming parasitic in the red blood cells.
Various hemorrhagic fevers are described in the highlands of Bolivia. These are considered to be viral in
origin, the virus belonging to the same group as that
which causes lassa fever. Hemorrhagic disorders have
also been described in north-eastern Nepal.
Mosquitoes, which transmit malaria and yellow
fever, are absent at high altitude, but typhus appears
to be commoner than at lower levels. This may be
because bathing is not usual at higher altitudes,
because of the cold, and so lice are common.
Pulmonary disease also appears common at altitude and this in part may be related to the exposure
of highlanders to the smoke from open fires inside
their houses or tents. In Xizang (Tibet) the incidence
of chronic bronchitis was 3.7 per cent in a low altitude population and 22.9 per cent in a population at

212 High altitude populations

4500 m. This was complicated by emphysema in

5-12 per cent of cases and by cor pulmonale in
0.98 per cent (Sun 1985). In Qinghai province,
chronic obstructive airway disease is relatively common but smoking is prevalent, particularly amongst
immigrants to high altitude. In the Pamir too, respiratory infections were noted by Forsyth (1875),
though they seem less common now.
In Nepal and throughout the subcontinent, pulmonary tuberculosis was relatively common,
whereas in Ethiopia it was rare. In Ethiopia the major
communicable diseases were measles, malaria,
dysentery, scabies and syphilis, and the total incidence of communicable disease was greater in the
low altitude population (Harrison et al. 1969).
In northern Bhutan, respiratory infections
appeared to be commoner in the younger age groups
but were rare in adults; antibodies to a number of
common viral infections were found. A high proportion of the population had been exposed to influenza,
mumps, measles, herpes simplex and the common
cold (Jackson etal. 1966, p. 96); in Lhasa, other parts
of Tibet and the Pamir, measles epidemics with a high
mortality have been reported in the past.
Leprosy occurs in Nepal and Bhutan (Ward and
Jackson 1965) and was reported in Tibet in the nineteenth century (Das 1902) and in the western
Himalayas (Moorcroft and Trebeck 1841, Vol. 1,
p. 180). The incidence of venereal disease appears to
have been high in Lhasa (Chapman 1938), south Tibet
and Bhutan (Saunders 1789) and in the Pamir
(Forsyth 1875). Where large flocks of sheep are found,
as in Qinghai province, hydatid disease is common.
European travelers in Central Asia (Deasy 1901,
Grenard 1904, p. 249) have also mentioned plague.
Chronic eye infections are seen in the populations
of the Pamir, Himalayas and Tibetan plateau; the
smoke of yak dung fires exacerbates them. Instruments for the treatment of cataract were available to
those who practiced traditional Tibetan medicine; in
general, surgery was not commonly carried out.
In summary, where certain infections are common
they are due to the low living standards of the people
rather than to altitude per se.

17.6,4

to the mountains, and over 200 million people

worldwide have goiter (Figure 17.1). Iodine deficiency is due to low iodine content of the soil and
therefore the water. Soils poor in iodine are found
where the land remained longest under quaternary
glaciers. When the ice thawed, the iodine-rich soil
was swept away and replaced by new soil derived
from iodine-poor crystalline rocks. Seaweed, which
is rich in iodine, and other folk remedies have been
used since ancient times for prophylaxis and treatment (Hetzel 1989).
Scientific proof that goiter was due to iodine deficiency was not available until Marine and Kimball
(1920) published a controlled trial in high school
children in Akron, Ohio. They showed a reduction in
the size of goiters and prevention of their development in children treated with iodine.
Iodine deficiency causes hyperplasia and retention
of colloid in the thyroid, resulting in goiter and,

Goiter

The frequency of goiter in mountainous areas has

been recognized for centuries, but it is not confined

Figure 17.1 Tibetan from north Bhutan with large pendulous

goitre.

Diseases 213

eventually, hypothyroidism in adults. Children born

to iodine-deficient mothers have a range of neurological and skeletal defects known collectively as
cretinism, an association noted for centuries. This
term covers a range of clinical conditions which seem
to vary in frequency and importance from locality to
locality and includes dwarfism, goiter, facial dysmorphism, deafness, deaf mutism and intellectual
impairment.
In populations with goiter, the overall work capacity of the population maybe impaired, as, in addition
to cretinism, there is a marked morbidity, infant
mortality is raised and mental subnormality common.
Iodine deficiency may result from insufficient
intake, goitrogenic substances and deficiency in
intrathyroidal enzymes; an excess of calcium or fluoride in the presence of iodine deficiency may increase
the incidence of goiter.
McCarrison (1908, 1913) carried out a classical
study of goiter and endemic cretinism in the Gilgit
Agency of Kashmir (Karakoram), and more recently
Chapman et al. (1972) worked in the identical area.
In 1906, McCarrison found a goiter incidence of
65 per cent; in Chapman's study it was 74 per cent. In
the latter study, 10 of 589 individuals examined were
cretins, and hypothyroidism, excluding cretinism,
was found in 24 subjects. Although the population as
a whole appeared to be iodine deficient, the majority
had adapted well. No evidence was found that goiter
was caused by an infectious agent, a theory put forward by McCarrison.
The incidence of goiter may vary widely within a
few miles; some 100 miles (160 km) north of Gilgit
where goiter was endemic, it was not observed in the
semi-nomadic Kirghiz tribesmen who inhabit the
Pamir plateau of southern Xinjiang. Direct questioning of the nomads revealed that they knew about goiter but they were adamant that there was no history
of its occurrence amongst them (Ward 1983),
though Marco Polo noted a large population of people with goiter in Yarkand (Shache) as did Forsyth
(1875). However, hearsay evidence is notably unreliable. Anecdotal evidence of goiter in other regions of
the Himalayas, the Shimshall region of the
Karakoram, and west Bhutan, suggests also that the
incidence may vary considerably within a few miles
(Saunders 1789, Shipton 1938).
Moorcroft and Trebeck (1841, Vol. 2), while traveling in the western Himalayas and on the Tibetan

border, comment on goiter that, 'scarcely a woman

was free from it' (p. 25). Later they say, 'Goiter was
here very common: the water was soft whilst at Gonh
it was too hard to mix with soap: but so it was at Le
where goiter does not prevail' (p. 30). Eraser (1820)
alludes to surgical removal
We understand it (goiter) was sometimes cured
when early means were taken, and these are said to
consist in extirpation of the part by the knife. We
saw some persons who had scars on their throat
resulting from this mode of cure which had in these
instances been completely successful.

Waddell (1899), in a village where goiter was

prevalent, writes, 'I was surprised to see that several
of the goats and the domestic fowls, as well as some
of the ponies, had the same large swellings'.
According to Dr Sun Sin-Fu (personal communication), in Lhasa, about 60 per cent of Tibetan
indigenous inhabitants have goiter. Das (1902) commented too that Tibetan physicians recognized six
varieties of goiter. Rockhill (1891, p. 265) also
observed goiter, particularly in women in eastern
Tibet, and other travelers noted the condition in
northern Tibet (Bonvalot 1891, p. 116) and in the
gorge country of south-east Tibet (Bailey 1957).
The incidence of goiter in Himalayan valleys is
high, and in the Tibetan ethnic population of north
Bhutan it was the commonest clinical condition. In
subjects less than 20 years old it was less marked, and
younger individuals had a diffuse enlargement,
whereas with age a nodular goiter was more common. No cases of cancer or thyrotoxicosis were seen,
and two cretins were found in 349 individuals examined. The incidence of goiter was 60 per cent in
females and 19 per cent in males (Jackson et al. 1966,
pp. 40-4).
Ibbertson et al (1972), in a survey of Sherpas (also
of Tibetan ethnic origin) in the Sola Khumbu region
of north-eastern Nepal, found that 92 per cent had a
palpable goiter, which was visibly enlarged in
63 per cent; 75 per cent had below normal proteinbound iodine levels in the blood and 30 per cent were
clinically hypothyroid. Classical myxedema was present in 5.9 per cent of the population, deaf mutism in
a further 4.7 per cent and isolated deafness in a further 3.1 per cent. Pitt (1970) describes Nepalese
babies born with goiter. In many of these areas the
incidence of goiter is much lower now after various
projects for giving iodine by tablets or depot injec-

214 High altitude populations

tions have been carried out. In a survey carried out in

1980-1 in Ethiopia, the gross goiter prevalence was
found to be 30 per cent among schoolchildren and
19 per cent in household members (Wolde-Gebriel
etal 1993).

17.6.5

going to altitude (section 27.4.3). Adzaku et al.

(1993) attribute the relative well being of their
patients at altitude to their high 2,3-DPG, which, at
this relatively modest altitude, would help tissue
oxygenation, in contrast to the situation at extreme
altitude (Chapter 12).

Sickle cell disease

17.6.6

Adzaku et al. (1993) reported on 136 patients resident at about 3000 m in Saudi Arabia and compared
them with 185 patients living at sea level. Patients at
both locations included those with homozygous disease (Hb SS), hemoglobin C (Hb SC) and sickle cell
trait (Hb AS). The main finding was a marked
increase in 2,3-diphosphoglycerate (2,3-DPG) in
patients with sickle cell disease compared with normal controls at altitude and patients at sea level.
Their hemoglobin concentration was not different
from sea level patients; they were anemic, with
values around 8.0-9.0 g dlr1. Sickle cell patients
resident at low altitude have a high risk of crises on

Dental conditions

There is no evidence that altitude has any direct

effect on the teeth but the economic conditions, dictated in part by altitude, may well affect diet and
hence dental condition. Generally the diet of high
altitude populations contains less refined sugars and
more fiber, giving fewer caries than a more 'western'
diet. Green (1992) reported a much higher incidence
of caries amongst Sherpa children along the popular
trekking routes in Nepal (76 per cent) than in villages
off the routes (17 per cent). The latter had not had
the 'benefit' of cadging sweets from generous but
misguided tourists.

18
Acute mountain sickness
18.1
18.2
18.3
18.4

Introduction
Definitions and nomenclature
Incidence of benign AMS
Etiology

215
216
217
218

SUMMARY
Acute mountain sickness (AMS) commonly afflicts
otherwise healthy men and woman who go rapidly to
altitude. Symptoms, which come on a few hours after
arrival, include headache, anorexia, nausea, vomiting, lack of energy, malaise and disturbed sleep. The
symptoms are usually worst on days 2 and 3 at
altitude and disappear by day 5. Symptoms may
reappear on ascent to a higher altitude. This
common self-limiting condition is termed simple or
benign AMS. Two other forms of AMS are high
altitude pulmonary edema (HAPE) and high altitude
cerebral edema (HACE) which are the subjects of
Chapters 19 and 20 respectively. These 'are
potentially lethal and can be termed malignant AMS.
The incidence of AMS depends upon the rate of
ascent and the height reached. It is uncommon below
2000 m but is almost universal among those flying
directly to altitudes above 3800 m. It occurs in both
sexes and at all ages. Fitness confers no protection and
so far no physiological measurement gives reliable
prediction of susceptibility for AMS. Strenuous
exercise on arrival at altitude is possibly a risk factor,
especially for HAPE. The mechanism underlying the
symptoms is still debated but cerebral edema is considered the most likely immediate cause. The edema
is probably due to vasogenic mechanisms in which
cerebral blood flow and permeability play a part.
There may be roles for fluid and sodium balance, also

18.5
18.6
18.7
18.8

Mechanisms
Prophylaxis
Treatment
Scoring AMS symptoms

221
226
229
231

for ventilation and its control in the mechanism of

AMS. Subclinical pulmonary edema through its effect
on blood gases may also be important.
Though there is debate about the mechanisms of
AMS there is a consensus about its management. AMS
can be prevented or ameliorated by a slow rate of
ascent and by drugs, of which acetazolamide is the
best studied and most widely used. Other drugs,
including spironolactone, probably also help.
Treatment is hardly needed in the majority of cases
but ibuprofen and dexamethasone have been shown
to be effective in the relief of headache; acetazolamide
is also helpful as treatment and improves blood gases.
An agreed scoring system for AMS has been
devised, the Lake Louise system, which is recommended for research into AMS. It is described at the
end of the chapter.

18.1

INTRODUCTION

It has been known for many years that travelers to

high mountains experience a variety of symptoms:
an early description was given by de Acosta (Chapter
1.3). The first modern account of AMS was by
Ravenhill (1913). He pointed out that fatigue, cold,
lack of food, etc. complicated previous descriptions
by explorers and mountain climbers. He was serving
as a medical officer of a mining company whose
mines at 4700 m in Chile were served by a railway, so

216 Acute mountain sickness

that the patients he observed were suffering the

uncomplicated effects of altitude alone. The local
Bolivian name for AMS was puna; in Peru it was
soroche. Tibetan names for AMS include ladrak (poison of the pass) damgiri, duqri, yen chang (from the
Koko Nor region), chang-chi (from Szechuan), and
tuteck. Ravenhill's description of simple AMS, which
he calls puna of the 'normal' type, can hardly be bettered. He wrote:
It is a curious fact that the symptoms of puna do not
usually evince themselves at once. The majority of
newcomers have expressed themselves as being
quite well on first arrival. As a rule, towards the
evening, the patient begins to feel rather slack and
disinclined for exertion. He goes to bed but has a
restless and troubled night and wakes up next
morning with a severe frontal headache.

acute pulmonary edema and acute cerebral edema of

high altitude (section 18.2).
After Ravenhill, although mountain sickness was
well recognized, the distinction and importance of
the two complicating forms seem to have been lost,
at least in the English-speaking world, until rediscovered by Hultgren and Spickard (1960) and
Houston (1960) in the case of HAPE and by Fitch
(1964) for HACE. However, HAPE was well known
to South American physicians with experience at
altitude. Lizarraga (1955) gave the first detailed
description of the condition after Ravenhill. A fuller
account of the history of AMS is given in West (1998,
pp. 132-63).

18.2
DEFINITIONS AND
NOMENCLATURE

There may be vomiting, frequently there is a sense

of oppression in the chest but there is rarely any
respiratory distress or alteration in the normal rate
of breathing so long as the patient is at rest. The
patient may feel slightly giddy on rising from bed
and

any

attempt

at

exertion

increases

the

headache, which is nearly always confined to the

frontal region (Ravenhill 1913)

To this description should be added the symptoms

of irritability and occasionally photophobia. Sleep is
often disturbed, probably because of periodic
breathing. The patient may wake with a feeling of
suffocation during the apneic phase. It should be
noted, however, that periodic breathing is not a
symptom of AMS. At altitudes above about 5000 m it
continues in many subjects long after any symptoms
of AMS have resolved and there is no correlation
between its severity and AMS scores (Eichenberger et
al. 1996). It is not a cause of AMS though its
presence, by causing more severe intermittent
hypoxia, may make matters worse. Ravenhill then
goes on to describe puna of the cardiac and nervous
types, corresponding in our present nomenclature to

The nomenclature of mountain sickness is summarized in Table 18.1. The terms puna and soroche
are used loosely in South America, not only for the
symptoms of AMS but also for the dyspnea normal
to exertion at high altitude (Ravenhill 1913). They
are also used for chronic mountain sickness, a
completely distinct clinical entity (Chapter 21). The
term 'mountain sickness' needs to be qualified by the
word 'acute' to distinguish it from this latter entity;
the term 'acute mountain sickness' is now well
accepted for this condition or group of conditions.
Finally there is the recently described subacute
mountain sickness affecting either infants or adults
(Chapter 21).
Dickinson (1982) made the useful suggestion that
the 'normal' or 'simple' AMS, which commonly
affects most people going rapidly to high altitude and
which is self-limiting, be termed 'benign', whereas
the other two forms or complications of AMS be
termed 'malignant', since they are life threatening.
They are thus termed 'malignant pulmonary AMS'
and 'malignant cerebral AMS'.

Table 18.1 Nomenclature of mountain sickness

Ravenhill (1913)

Puna of the normal type Puna of the cardiac type

Puna of the nervous type

Dickinson (1982)

Benign AMS

Malignant pulmonary AMS

Malignant cerebral AMS

Others

Simple AMS

High altitude pulmonary

edema (HAPE)

High altitude cerebral

edema (HACE)

Chronic mountain
sickness (CMS)

Incidence of benign AMS 217

However, this terminology, emphasizing the

crucial difference between the forms of AMS, has
not been widely adopted. The terms more commonly used for the malignant forms are HAPE and
HACE. Many cases of malignant AMS include
features of both pulmonary and cerebral edema.
There is a strong impression that HACE is an
advanced form of simple AMS. The symptoms of
both are due to cerebral edema. The difference is
that in simple AMS the edema is self-limiting and
reverses even at altitude, but in HACE it is progressive. HAPE has different mechanisms from
simple AMS, involving pulmonary hypertension,
and is more clearly a condition of individual
susceptibility.

18.2.1

Definition, signs and symptoms

Benign AMS may be defined as a self-limiting

condition affecting previously healthy individuals on
going rapidly to high altitude. After arrival there may
be an asymptomatic period of some 6-12 h.
Symptoms, including headache, anorexia, nausea,
vomiting, fatigue, light-headedness and sleep
disturbance, then start gradually and usually peak on
the second or third day. By day 4 or 5 symptoms are
usually gone and do not recur at that altitude. The
Lake Louise scoring system (section 18.8) requires
mild headache and at least one of the above
symptoms to make the diagnosis as well as a score of
3 or more. There must be a history of recent height
gain and (if altitude is reached abruptly as by air or
cable car) several hours must elapse before the
symptoms start. The diagnosis is made on the history
and there may be no signs. However, physical
examination may reveal crackles in the chest and
peripheral edema. This may show as periorbital
edema after sleep or as ankle edema after being up
and about (Figure 18.1). According to Hackett and
Rennie (1979) the proportions of cases showing
these signs were 23 per cent and 18 per cent
respectively. Mild fever may be present. Maggiorini
et al. (1997) found a rise in body temp of 0.5 C in
mild cases (AMS score = 3), 1.2 C in more severe
cases of AMS (score >3) and 1.7 C in cases of HAPE.
With the advent of small, portable pulse oximeters,
Sa02 can be measured easily and this value is often
low both in patients with AMS and in subjects who
will subsequently develop AMS (section 18.4.8).

Figure 18.1 (a) Pitting edema of ankle after hill walking at low
altitude, (b) Periorbital edema at high altitude.

Ascent to a higher altitude, even after acclimatization at a lower altitude, may precipitate a further
attack. Descent and re-ascent after less than
7-10 days does not usually provoke symptoms but
descent for more than about 10 days renders the
subject susceptible to AMS on re-ascent. The period
of risk for AMS therefore corresponds with the
period before acclimatization has taken place.
Acclimatization prevents AMS, though it is not clear
how.

183

INCIDENCE OF BENIGN AMS

The incidence of AMS depends on the rate at which

people ascend to altitude and the height reached as

218 Acute mountain sickness

well as the exact definition of the condition. The

lowest altitude at which some individuals can be
affected is as low as 2000 m, the height of many ski
resorts. Rapid ascent to 3100 m, for instance by the
railway to the Gornergrat in Switzerland or by road to
Leadville, Colorado, produces symptoms in a
proportion of people by the next morning. Hackett
and Rennie (1979) found an overall incidence of
43 per cent in trekkers reaching the aid post at
Pheriche (4243 m), though some affected trekkers
would have dropped out before reaching this altitude.
Among those who flew into the airstrip at Lukla
(2800 m), the incidence was higher than among those
who walked all the way (49 per cent versus 31 per
cent). Maggiorini et al (1990) found incidences in
climbers to European alpine huts of 9 per cent at
2850 m, 13 per cent at 3050 m and 34 per cent at
3650 m. A study of a general tourist population
arriving at resorts in Colorado at altitudes of
1900-2940 m found an incidence of 25 per cent
(Honigman et al. 1993). Among lowlanders who
drive directly from Lima to Cerro de Pasco (4300 m)
in Peru or who fly to La Paz in Bolivia (3700 m) there
are very few who do not have at least mild symptoms
on the morning after arrival. Murdoch (1995)
reported an incidence of 85 per cent in tourists flying
into the airstrip at Shayangboche (3800 m) in Nepal.
However, if the stay at altitude is only an hour or
two the incidence of AMS is negligible. This is the
case, for instance, for the great majority of tourists
who drive or take the train to the summit of Pikes
Peak, Colorado (4300 m).

18*4
18*4*1

ETIOLOGY
Individual susceptibility

The etiology of AMS is multifactorial. The most

important factors are the rate of ascent and the
height reached. Symptoms can be induced in almost
all subjects if ascent is made rapidly to a sufficient
height, but for any given altitude/time profile there is
great variation in individual susceptibility.
18*4*2

AMS and fitness

There is no easy way to identify the susceptible individual, as Ravenhill (1913) says:

There is in my experience no type of man of whom

one can say he will or will not suffer from puna.
Most of the cases I have instanced were young men
to all appearances perfectly sound. Young, strong
and healthy men may be completely overcome.
Stout, plethoric individuals of the chronic
bronchitic type may not even have a headache. I
have known several instances of this even when the
persons

have

taken

no

care of

themselves

(Ravenhill 1913).

Certainly athletic fitness provides no immunity. A

superbly fit French paratrooper on a family trek to
Everest Base Camp had to be evacuated to lower
altitude with severe symptoms of AMS while his
mother and aunt were unaffected (Milledge, B.A.
personal communication). One study found no
correlation between fitness as measured by V02max
before an expedition to Mount Kenya and AMS
symptom scores during the first days at altitude
(Milledge et al 199la). Bircher et al. (1994), in a
study of 41 mountaineers who went to 4559 m in the
Alps in 20-22 h, found no correlation between a
measure of fitness (PWC170) and AMS scores, and
Savourey et al. (1995) similarly found no correlation
between V02max and subsequent AMS on an Andean
expedition.
18*4*3 Consistency in response to
altitude
Individuals respond reasonably consistently, so that
performance on one occasion is a guide to future
performance. This clinical impression has been
confirmed in a study by Forster (1984), who studied
workers at Mauna Kea observatory in Hawaii,
situated at 4200 m. These workers alternated 5 days
at the observatory with 5 days at sea level so Forster
was able to score the symptoms of AMS in 18 men on
two altitude shifts. He showed that the rank order of
scores correlated significantly on the two occasions.
There is a tendency to acclimatize better on each
subsequent trip to altitude.
However, there are numerous exceptions and case
histories do show anomalies. For instance, someone
who has had little trouble on the first two trips may
develop AMS on a third. A respiratory or some other
infection may be an added factor in such cases. The
consistency in response is greater in the case of individuals who have had HAPE.

Etiology 219

18.4.4
build

AMS, gender, age and body

Both men and women are at risk. One study (Kayser

1991) of trekkers going over the Thorong pass in
Nepal (5400 m) found women to have a higher rate
of sickness than men (69 per cent versus 57 per cent),
but perhaps women are more ready to admit to
symptoms than men. The young are probably at
greater risk than the old (Hackett et al. 1976, Roach
et al. 1995) and the risk among boys, at least of
HAPE, seems especially high in South America
(Hultgren and Marticorena 1978). However, Yaron
et al. (1998) found an incidence of benign AMS in
young children similar to that in adults.
Subjects slimmer than average (body mass index
< 22) may be less susceptible to AMS than those who
are standard or obese, according to one study (Hirata
et al. 1989); Kayser (1991) also found obesity to be a
risk factor in men.
18.4.5

Smoking, diet and AMS

There has been an impression amongst mountaineers

that smokers have less AMS than nonsmokers
perhaps because, being habituated to a modest level
of carboxyhemoglobin, they have, in effect, some preacclimatization. A recent chamber study (Yoneda and
Watanabe 1997) seems to confirm that, at least for
very acute, severe hypoxia, smokers had fewer
symptoms, though their time of useful consciousness
was not different from that of nonsmokers.
A high carbohydrate diet has some physiological
benefit at altitude (section 14.8.1) and is preferred by
many mountaineers, but does it reduce AMS? In a
chamber study of 19 subjects given either a high
(68 per cent) or normal (45 per cent) carbohydrate
diet for 4 days before altitude exposure for 8 h,
Swenson et al. (1997) found that there was no
difference in the AMS scores between the two diets.
18.4.6 AMS and hypoxic ventilatory
response (HVR)
There is some evidence that subjects with a low HVR
(Chapter 5) measured at sea level are liable to
develop AMS. The association has been shown by
measurements of the response to acute hypoxia in
the laboratory in studies of a few subjects

(Lakshminarayan and Pierson 1975, Hu et al. 1982,

Matsuzawa et al. 1989). In the last study, 2 of the 10
subjects had HVR within the normal range.
Richalet et al. (1988) studied a large group of
climbers before they went on various expeditions to
the great ranges. They found that low ventilatory and
cardiac responses to hypoxia on exercise were risk
factors for AMS. The same group recently reported a
single case of high susceptibility in a subject who had
had radiation to his neck as a child and had a very low
HVR (presumably because of damage to his carotid
bodies). He suffered severe AMS at only 3500 m
(Rathat et al. 1993). However, a number of more
recent studies in the field have failed to find a correlation. Two prospective studies found no correlation
between HVR measured before going to altitude and
symptom scores for AMS after arrival (Milledge et al.
1988, 1991b). Savourey et al. (1995) recently also
reported no correlation with HVR measured before
an Andean expedition and subsequent AMS.
Interestingly, they did find that resting P02 at sea level
or at simulated altitude was predictive for AMS.
Selland et al. (1993) found that two of four subjects
with a history of HAPE had HVR greater than their
control subjects' mean value. Hackett et al. (1987b) in
a study of 106 climbers on Mount McKinley found
that, although a low Sa02 predicted the likely development of AMS, there was no good correlation between
HVR and 5a02 on arrival at altitude. Hohenhaus et al.
(1995) found that, compared with control fit subjects,
HVR was significantly lower in subjects who
developed HAPE but not in subjects with AMS.
Highlanders, who generally have less AMS than lowlanders, have a blunted HVR (section 5.5.2).
Interestingly, Hackett et al. (1988b) found an abnormal (negative) HVR at altitude in patients with
HAPE. They seemed to have hypoxic depression of
ventilation, which was relieved by oxygen breathing.
In conclusion, it would seem that although
susceptibility to HAPE is associated with a low HVR,
susceptibility to AMS is not.

18.4.7 AMS hypoxic pulmonary artery

pressor and cerebral blood flow
responses
A brisk increase in pulmonary artery pressure in
response to hypoxia is possibly also a risk factor for
AMS (Hultgren et al. 1971, Kawashima et al. 1989),

220 Acute mountain sickness

although doubt is cast on this by the finding that

nifedipine, which by lowering the pulmonary artery
pressure is protective of HAPE, does not protect
from AMS (Hohenhaus et al. 1994). The measurement of pulmonary artery pressure noninvasively
with Doppler ultrasound in a short hypoxic test
might be useful in identifying those subjects
susceptible to HAPE since they have an abnormally
brisk response (section 19.2.8).
A recent study looked at the cerebral blood flow
response to a 15-min hypoxic and hyperoxic
challenge in one group of subjects who had suffered
HAPE, another who had been to altitude with no
AMS and a third unselected control group. The test
was found not to be predictive of altitude tolerance
(Berreeta/. 1999).

18.4*8

Oxygen saturation and AMS

Although hypoxia is not the immediate cause of the

symptoms of AMS, the severity of hypoxia is
important since the incidence increases with altitude.
It is perhaps not surprising, therefore, that a number
of studies have shown a correlation between Sa02 and
AMS (Bircher et al. 1994, Roach et al. 1998). In the
study by Bircher et al. subjects traveled to the
Capanna Margherita (4559 m) in the Alps by helicopter and the saturations were measured on the second day when AMS symptoms were at their height.
Some subjects had overt HAPE and no doubt others
had subclinical edema. In the study by Roach and
colleagues, 102 climbers on Mount Denali in Alaska
were studied at Base Camp (4200 m) and then questioned about AMS symptoms on their return from
their summit bids. The Sa02 measured before climbing from Base Camp correlated with subsequent
AMS scores. Thus a low Sa02 on arrival at altitude is a
good predictor for the later development of AMS.
The authors comment that the reason for the low
5a02 in these subjects could be either hypoventilation
or impaired gas exchange. However, Bircher et al.
(1994) did not find a difference in Pac02 between
those with and without AMS and the collected results
from over 90 subjects from a number of studies at
this location by Bartsch (personal communication)
gave the same finding. However, other studies,
mostly taking measurements earlier in altitude exposure, did find evidence of hypoventilation and higher
PC02 in AMS subjects (section 18.5.2).

Another way of looking at the possible gas

exchange abnormality was studied by Ge et al. (1997)
who measured pulmonary diffusing capacity for
carbon monoxide (Dco) in a group of 32 subjects at
2260 m and after ascent to 4700 m. In non-AMS
subjects there was an increase in Dco at the higher
altitude whereas in AMS patients the increase was
insignificant. They also showed lower vital capacity
(FVC), reduced expiratory flow in the middle of their
FVC and greater (A-a)O2 gradient. These differences
were thought to be due to subclinical pulmonary
edema. Pollard et al. (1997) also found reduced FVC
and forced expiratory volume one second (FEV,) at
altitude and a correlation between these indices of
lung function and arterial saturation. Probably a
degree of subclinical pulmonary edema is common
during the early days at altitude; and Anholm et al.
(1999) found radiographic evidence of pulmonary
edema in some well trained cyclists after an
endurance ride at moderate altitude.

18.4*9

Exercise and AMS

AMS can and frequently does occur in the absence of

any exercise, as in chamber experiments, or with only
gentle walking short distances, as in helicopter
transport to a mountain hut or a flight to La Paz,
Bolivia. But until recently we could not answer the
question of whether subjects climbing on foot to
altitude would be more or less likely to have AMS than
those who arrived there by air or motor transport
given the same rate of ascent. Obviously, most people
who fly to altitude have a more rapid height gain than
those who walk and therefore more AMS. Again, the
advice to people on arrival at altitude is to avoid exercise for some time but there are few hard data to support this. Bircher et al. (1994) did not find any
difference in the incidence of AMS in relation to
intensity of work (as assessed by heart rate) in groups
of subjects who climbed to the Capanna Margherita.
However, as the authors say, their study was not
designed to look at this relationship and the differences in exercise rates were not great. Roach et al.
(2000) carried out a crossover trial in which subjects
were exposed to 4572 m altitude equivalent in a chamber for 10 h on one occasion with and on another
without exercise. The AMS scores were significantly
higher during the exposure with exercise. This one
study lends some credence to the time-honored

Mechanisms 221

advice to avoid strenuous exercise in getting to and on

arrival at altitude, in order to avoid AMS. The same
advice is probably even more pertinent in relation to
HAPE where exercise raises pulmonary artery pressure and increases the risk of HAPE.

18.5
18.5.1

MECHANISMS
Fluid balance and AMS

Clearly hypoxia is a crucial starting mechanism for

AMS but it is not the direct cause of symptoms.
Within a few minutes of exposure to high altitude P02
falls throughout the body, but symptoms of AMS are
delayed for at least a few hours. This suggests that
hypoxia initiates some process which requires a time
course of 6-24 h before it, in turn, causes the
symptoms.
Current thinking favors the hypothesis that
hypoxia causes some alteration of fluid or electrolyte
homeostasis with either water retention or shifts of
water from intracellular to extracellular compartments (Hansen etal. 1970, Hackett etal 1981).
In considering the possible role of disturbances in
fluid balance in the mechanism of AMS we need to
take into account two other variables apart from the
rate of ascent:
whether or not the subject exercises in getting to
altitude or on arrival
whether the subject has a physiological or a
pathological response to altitude hypoxia; that is,
whether or not he gets AMS.
Table 18.2 shows the effect on various fluid compartments of exercise (hill walking at low altitude)

and of going to altitude and responding physiologically or pathologically.

EXERCISE AT LOW ALTITUDE

The effect of day-long exercise (hill walking) continued for several days at low altitude was studied in the
hills of north Wales. Full measurements of water and
electrolyte balances were carried out before, during
and after the exercise period. There was significant
sodium retention, modest water retention, significant increases in plasma and interstitial fluid
volumes at the expense of the intracellular compartment (Williams et al. 1979). In a later study this was
shown to be due to activation of the reninaldosterone system during exercise (Milledge et al.
1982; see section 15.3.3). The increased interstitial
fluid volume can cause overt pitting edema in a few
subjects (Figure 18.1) but all were in a state of subclinical edema.
ALTITUDE WITHOUT EXERCISE OR AMS

It is surprisingly difficult to obtain reliable data on

the effect of altitude on fluid and electrolyte balance
in the absence of exercise and AMS. Papers usually
indicate if exercise has been excluded (though not
always) but seldom make it clear which, if any,
subjects were free of AMS. Few papers quote strict
balance studies and those that do often give conflicting results. It is usually considered that the physiological response to hypoxia is a diuresis. This seems
to be the case in animals and is effected by stimulus
of the peripheral chemoreceptors (Honig 1989) but
is less easy to demonstrate in humans. Studies in the
field have given conflicting results, probably because
of the difficulty in controlling factors such as temper-

Table 18.2 Changes in sodium and water control with exercise at low altitude and in
response to altitude in subjects with and without AMS

Urine volume
Water balance
Sodium excretion
Plasma volume
Extracellular volume
Plasma aldosterone

4
? Positive
I
t
t
t

t
? Negative
t
I

I
i

i
? Positive

I
?T
?T
T

222 Acute mountain sickness

ature, sweating, sodium and water intake. However,

Swenson et al. (1995), in a 6-h chamber study where
these factors have all been controlled, have shown
that there was an increase in urinary volume and
sodium output with hypoxia. Further they found a
good correlation between these two measurements
and the individual's HVR. There were only minimal
symptoms of AMS in the 6 h of the study. The diuresis and natriuresis did not correlate with changes in
aldosterone, renin, atrial natriuretic peptide (ANP),
vasopressin or digoxin-like immunoreactive substance.
There is a reduction of plasma, interstitial and
intracellular volumes during the first few days at
altitude (Frayser et al. 1975, Jain et al. 1980). Similar
changes were found in a study by Singh et al. (1990)
and are shown in Figure 18.2. Note that the changes,
as a percentage of sea level values, are quite small, the
greatest being a 6-7 per cent reduction in plasma and
extracellular fluid (ECF) volumes at 2 days. The

changes in these compartments remained for up to

12 days whereas the reductions in total body water
and intracellular fluid were restored by day 12 at
altitude.
ALTITUDE WITH EXERCISE AND WITHOUT
AMS

A study based on the Gornergrat (3100 m),

Switzerland, involved baseline studies at rest at low
altitude followed by exercise in climbing to the
Gornergrat and daily while there (Milledge et al
1983d). Full balance studies were continued
throughout. The results were almost identical to
those of exercise at low altitude. The plasma volume
increased so that the hematocrit, instead of rising as
is usual at altitude, actually fell as it did at sea level.
Renin and aldosterone levels were high whereas
subjects at rest at altitude have low aldosterone levels.
The effect of exercise overrides the effect of altitude
in this situation.
ALTITUDE WITH EXERCISE AND AMS

There are no balance studies that have addressed

exactly this question, owing to the formidable
problems of carrying out balance studies on
sufficiently large numbers of subjects to cover both
good and bad acclimatizers. Studies measuring just
24-h sodium excretion have shown an inverse
correlation between sodium excretion and AMS
symptom scores and a direct correlation with aldosterone concentration. That is, those who develop
AMS have higher aldosterone levels and retain more
sodium. All subjects have a reduced urine volume,
with the AMS victims tending to have a greater
antidiuresis but this did not reach statistical significance (Bartsch etal 1988, Milledge etal 1989).
SODIUM AND WATER BALANCE IN AMS

Figure 18.2 Changes in fluid compartments on going to altitude

in the absence of exercise or AMS. ICF, intracellular fluid volume;
IntF, interstitial fluid volume; TBW, total body water; B wt, body
weight; ECF, extracellular fluid volume; PV, plasma volume. (Data
from Singh et al. 1990.)

Table 18.2 attempts to bring together these changes,

showing that the subject with AMS is in a similar
state of expanded plasma and ECF volume as a
subject starting day-long exercise at low altitude.
They are both in a state of subclinical edema.
These effects are shown in Figure 18.3, on the left.
It is suggested that this increase in ECF in turn results
in the dependent and periorbital edema often seen in
patients with AMS (Hackett and Rennie 1979). It
also causes mild cerebral edema, resulting in the

Mechanisms 223

Figure 18.3 Possible mechanisms underlying acute mountain

sickness (AMS). ICF, intracellular fluid; ECF, extracellular fluid; CBF,
cerebral blood flow; ANP, atrial natriuretic peptide.

symptoms of AMS. More severe cerebral edema

causes the full-blown malignant condition of RACE
and pulmonary edema causes HAPE.
Some evidence of fluid retention is provided by
the clinical observation of lower urine output in
soldiers with AMS than in soldiers free of symptoms
(Singh et al. 1969b) and by the finding that trekkers
with the condition gained weight, whereas trekkers
without AMS had lost weight by the time they
reached 4243 m (Hackett et al. 1982). The 'normal'
response to altitude seems to be a mild diuresis,
whereas subjects destined to get AMS have an antidiuresis.

Because of this antidiuresis the antidiuretic

hormone (vasopressin) might be thought to underlie
this mechanism but that seems not to be the case; see
section 15.2.3. The effect of altitude on the reninaldosterone system is reviewed in section 15.3.
Briefly, ascent to altitude alone has a variable effect
on plasma renin activity but results in lower than
normal aldosterone levels at rest. Exercise stimulates
the release of renin which in turn, via angiotensin,
stimulates aldosterone release and - if continued
long enough - causes salt and hence water retention
(Williams et al 1979, Milledge et al. 1982). This may
be important especially in HAPE, in which a history
of exercise is often a prominent feature (Chapter 19).
AMS symptom scores were found to correlate with
aldosterone levels and with reduced 24-h urine
sodium output on the first day at altitude in subjects
who had ascended to 4300 m on foot on Mount
Kenya (Milledge et al. 1989). A similar result was
reported from a study in the European Alps (Bartsch
et al. 1988) although Hogan et al. (1973), in a
chamber experiment, found that subjects with AMS
had lower aldosterone concentrations than did
asymptomatic subjects.
ANP, which increases urinary sodium excretion
and hence fluid excretion, is elevated by hypoxia in
rats (Winter et al. 1987a) and humans (Bartsch et al.
1988, Cosby et al. 1988, Milledge et al. 1989). The
relationship between ANP levels and AMS is variable. One study found a tendency to higher levels in
subjects more resistant to AMS (Milledge et al. 1989)
whereas two other studies found the opposite
(Bartsch et al. 1988, Cosby et al. 1988). It seems that
despite its name ANP is not a very powerful natriuretic hormone. Subjects hill walking at low altitude
have raised ANP levels while retaining sodium vigorously (Milledge etal. 1991b). ANP may have an effect
by increasing capillary permeability but its significance in the etiology of AMS remains to be established (Bartsch etal. 1988).
Although, as mentioned, the favored hypothesis is
that fluid is retained and somehow causes AMS, it has
proved very hard to obtain good evidence for this.
Measurements of urine output have usually not
shown a clear difference between those with and
without AMS (Milledge et al. 1989), though this
negative finding often goes unreported. Westerterp et
al. (1996) applied the technique of labeled water and
bromide to the problem. A group of 10 subjects was
transported by helicopter to the Vallot observatory

224 Acute mountain sickness

(4350 m) on Mont Blanc and studied for 4 days. Fluid

intake correlated closely with food intake and both
were reduced in those with AMS. There was reduced
evaporative water loss at altitude which resulted in
increased urine output in the case of subjects without
AMS but not in AMS sufferers. The change in total
body water was small and not significantly different
between those with and without AMS. However,
those with AMS showed a fluid shift greater than 1 L
between intracellular and extracellular compartments. The shift could be in either direction, making
it difficult to understand the mechanism. However,
only one AMS subject had a reduction in extracellular volume while three showed the expected increase.

18.5,2 Role of PC02 in AMS and cerebral

blood flow
On going to high altitude the subject experiences not
only hypoxia but also hypocapnia. The possibility
that hypocapnia over a number of hours might be a
factor in the genesis of AMS was tested by Maher et
al. (1975c). They exposed two groups of subjects to
simulated altitude in a hypobaric chamber. One
group had carbon dioxide added to the atmosphere
to maintain their PC02 at control levels; the other
group breathed air and became hypocapnic. Hypoxia
was similar in the two groups, though to achieve this
the group with carbon dioxide added was taken to a
lower barometric pressure. Far from alleviating
symptoms of AMS, the added carbon dioxide
increased their severity.
Sutton et al. (1976) found that in a group of
subjects air lifted to a camp at 5360 m on Mount
Logan in the Canadian Yukon, the severity of AMS
correlated best with the PC02. Forwand et al. (1968)
found AMS symptom scores correlated well with
Pcc,2 but not with pH or P02. In a study of 42 trekkers,
Hackett et al. (1982) found that those who gained
weight on ascent to 4300 m had the highest incidence
of AMS and reduced their Pac02 very little, whereas
those who lost weight (presumably mainly fluid) had
less frequent AMS and a low -PAC02. Two studies of
men in decompression chambers also found a correlation between AMS and hypoventilation (King and
Robinson 1972, Moore et al. 1986). Maher et al.
(1975) suggested that the mechanism connecting
PCo2 and AMS was the well-known effect of carbon
dioxide in increasing the cerebral blood flow.

Hypoxia also causes an increase in cerebral blood

flow. In subjects with a brisk ventilatory response
and low PC02 these two effects are, to a degree,
counterbalanced, whereas in subjects with little
increase in ventilation and Pco2 close to sea level
normal, cerebral vessels will be dilated and may
contribute to cerebral edema and a rise in intracranial pressure. This is turn causes the symptoms of
AMS and is shown in Figure 18.3 on the right of the
diagram. Another possibility, referred to above, is
that the higher PC02 and lower P02 would cause
peripheral vasodilatation which, by lowering central
venous pressure, would lower the level of ANP and
result in an antidiuresis. Cerebral blood flow is
increased on going to altitude and falls towards sea
level values with acclimatization (Severinghaus et al.
1966b). One study, which confirmed this general
pattern, found no difference in cerebral blood flow
between subjects with and without AMS symptoms
(Jensen et al. 1990). However, two more recent
studies (Baumgartner et al. 1994, Jansen et al. 1999),
using velocity in the middle cerebral artery measured
by Doppler ultrasound, have shown greater increase
on going to altitude in subjects with AMS than in
nonsymptomatic controls. The 5a02 was lower in
AMS subjects and accounted for much of the difference in flow. However, Jansen et al. (1999) showed
that AMS subjects had greater response in flow to
changes in PC02 (voluntary hyperventilation) than
controls, suggesting brisker vasomotor response in
these susceptible individuals.

18.5.3

Intracranial pressure and AMS

There is a striking similarity of symptoms between

AMS and the effects of high intracranial pressure due
to cerebral tumors, etc. The evidence for raised
intracranial pressure in AMS is:
The CSF pressure was found to be elevated by
60-210 mm H2O during AMS compared with
that after recovery (Singh et al. 1969b).
In cases of malignant cerebral AMS, papilledema
has been noted (Dickinson 1979).
In those dying with cerebral AMS, cerebral
edema with flattening of the cerebral
convolutions has been found (Singh et al. 1969b,
Dickinson et al 1983).
Computerized tomographic examination of the
brain in patients with HACE showed diffuse low

Mechanisms 225

density areas in the cerebrum representing

edema (Fukushima etal. 1983).
Direct measurement has been made in one
unreported study (B. H. Cummings, personal
communication). One of three subjects with
pressure transducers implanted in their skulls
before a Himalayan expedition was mountain
sick on return from 5700 m to Base Camp at
4750 m. His intracranial pressure was normal at
rest but elevated on the slightest exertion. Other
subjects without AMS had normal pressures even
on exercise.
Using an indirect measure of intracranial
pressure (tympanic membrane displacement)
exposure to acute hypoxia at 3440 m was
associated with a rise in pressure. However, on
going to 4120 m and 5200 m the pressure
returned to sea level values. There was no
correlation between intracranial pressure and
AMS scores (Wright et al 1995).
Despite the lack of good direct evidence, the
consensus view seems to be that the symptoms of
AMS are best explained as being due to cerebral
edema and raised intracranial pressure (Hackett
1999). This is further considered in Chapter 20,
where other factors that may be involved in the
mechanism of cerebral edema are discussed.

18.5.4 Derangement of clotting

mechanism
In reports on necropsy material, the presence of
thromboses in lungs and brain figures prominently.
No doubt parts of the pathological picture are
secondary, such as the development of hyaline
membrane in the alveoli and possibly some thrombi,
but there is evidence of alterations in coagulation
associated with altitude (Singh and Chohan 1972b).
It has been suggested that thrombosis may form a
basis for the development of both pulmonary hypertension and edema (Dickinson etal. 1983). However,
Hyers et al. (1979) were unable to show differences in
activated coagulation between those who are
susceptible to pulmonary edema and more normal
individuals at altitude.
Bartsch etal. (1987) studied a range of clotting factors in 66 subjects presenting at the Capanna
Margherita (4559 m) with varying degrees of AMS.
They found that coagulation time, euglobulin lysis

time and fibrin (ogen) fragment E were normal in all

subject groups. Fibrinopeptide A (FPA), a molecular
marker of in vivo fibrin formation, was elevated in
patients with HAPE. However, FPA was not elevated
in subjects with simple AMS even with widened
(A-a)O2, suggesting early HAPE. They conclude that
the fibrin formation which takes place in HAPE is an
epiphenomenon and not causative.

18.5.5
AMS

Microvascular permeability and

Hypoxia may increase microvascular permeability

directly or via mediators. Numerous animal studies
have shown that hypoxia increases lymph flow with
variable results on the lymph/plasma ratio for protein.
The problem is to separate hemodynamic effects from
permeability itself. Staub (1986) has reviewed the
effect of hypoxia on microvascular permeability and
concludes that, 'On best analysis ... the change in
permeability is slight, albeit statistically significant'.
However, there is no really good animal model
and the failure to show an important change in an
animal which does not get HAPE in no way excludes
the importance of permeability changes in humans.
Three findings have served to strengthen the
evidence for some effect of hypoxia on microvascular
permeability:
Larsen et al. (1985) have shown in rabbits that
neither hypoxia alone nor the infusion of cobra
venom (which activates the complement system)
alone caused pulmonary edema. However, the
two insults together did cause permeability-type
pulmonary edema. This suggests the possibility
that hypoxia, with some other factor, may
increase microvascular permeability.
Schoene et al. (1986) and Hackett etal. (1986),
by analysing bronchoalveolar lavage and
pulmonary edema fluid respectively, have shown
conclusively that in HAPE the edema is of the
high protein permeability type rather than
hemodynamic. They also found significant levels
of leukotriene B4 and factors chemotactic for
monocytes in the lavage fluid, suggesting that the
release of these and other mediators of
inflammation may be involved in the mechanism
of HAPE.
Richalet et al. (1991) found a rise in plasma levels
of most of the six eicosanoids measured in

226 Acute mountain sickness

subjects taken abruptly to the Vallot observatory

on Mont Blanc (4350 m). All subjects had AMS.
The levels of these vasoactive mediators affecting
permeability had a time course parallel to that of
AMS symptoms.
Roach et al. (1996) measured urinary leukotriene
E4 in subjects taken to 4300 m with a 4-day
stopover at 1830 m. There was a significant
increase in levels of urinary leukotriene though
the correlation with AMS did not reach
significance. The authors conclude that
leukotrienes may be involved in the genesis of
AMS.
Most of these studies have concentrated on the
pulmonary microvascular permeability but the same
mechanism could affect microvascular permeability
generally, including cerebral microvessels and thus
contribute to cerebral edema as shown in Figure 18.3
(center). Hypoxia has been shown to increase
permeability of endothelial monolayers to a range of
proteins in vitro, though quite severe hypoxia
(12-19 mmHg) and incubation for 48-72 h were
needed to show the effect (Gerlach et al. 1992).
Proteinuria is also common during the first few
days at altitude, especially in subjects with AMS
(Chapter 15), and this may be due to increased
microvascular permeability in the kidneys (Winterborn et al. 1986). If increased permeability has a role
in AMS there is the question of whether it initiates or
continues the process. Kleger et al. (1996) investigated this by measuring the escape rate of [ 125 I]labeled albumin as well as various cytokines in the
plasma of 24 subjects taken rapidly to 4559 m altitude. Ten subjects developed AMS and four RAPE.
The authors found no significant increase in albumin
escape in any group of subjects. The only significant
increase in cytokine levels was in the HAPE patients
and that was of IL-6 on days 2 and 3 at altitude
when HAPE was established. Swenson et al. (1997)
measured a number of cytokines in the plasma of 19
subjects exposed to 10 per cent oxygen for 8 h. They
found no change in the concentration of the
measured cytokines by the end of the exposure time.
These findings suggest that if cytokines do play a role
in AMS it is probably in the development of the
illness towards HAPE or HACE. In Chapter 19 there
is further consideration of mechanisms in relation to
HAPE, some of which may also apply to benign
AMS.

18.5*6

Anorexia, leptin and AMS

Leptin, a recently discovered hormone, produces the

sensation of satiety and is thought to be important in
body weight regulation. Tschop et al. (1998)
measured its level in subjects in two field studies at
the Capanna Margherita (4559 m). They found it to
be elevated at altitude compared with sea level and to
be higher in subjects with AMS than in those without. The neuropeptide cholecystokinin (CCK) also
suppresses the appetite. Bailey et al. (2000) found it
to be increased in plasma from subjects with AMS
compared with subjects free of symptoms on the
Kangchenjunga Medical Expedition 1998.

18.6

PROPHYLAXIS

AMS only occurs during the first few days at a given

altitude. It seems, therefore, that acclimatization in
some way confers protection from AMS. Allowing
time for acclimatization is therefore the best way to
prevent AMS. There is an impression that there are
limits to acclimatization which vary for different
individuals. At altitudes above this limit a person is
therefore at risk of AMS, HAPE and HACE even after
acclimatization to lower altitudes has been achieved.

18.6.1

Rate of ascent

A slow rate of ascent will prevent AMS but, because

of the great variation in susceptibility to AMS, it is
not possible to be dogmatic in advice on rate of
ascent. A suggested rule of thumb is that, above
3000 m, each night should be spent not more than
300 m above the last, with a rest day (i.e. 2 nights at
the same altitude) every 2-3 days. In addition, anyone who experiences symptoms of AMS should go
no higher until they improve. It is not certain where
the rule originated, possibly from the epidemiological study of trekkers on the route to Everest Base
Camp (Hackett et al. 1976). Recently Murdoch
(1999) has looked for evidence of its efficiency in
preventing AMS in the same area. He surveyed 283
trekkers, asking about AMS symptoms and speed of
ascent. There are two clear messages from this study:
Firstly, that there is huge individual variation in
susceptibility. Half the trekkers ascending at the

Prophylaxis 227

very low mean rate of 100-200 m/day became

sick whereas almost half the trekkers ascending at
500-600 m/day remained free of AMS. Obviously
there was a process of self-selection, with those
feeling fine going fast and those feeling less well
going slowly.
Secondly, that, overall, the incidence of AMS was
higher the faster trekkers ascended.
Murdoch's conclusion is that, although the rule is
slower than is really necessary for many, if not most,
trekkers, it should continue to be the guideline, in
the interest of a substantial minority. Basnyat et al.
(1999) also found evidence from their questionnaire
survey of the same trekking route that rate of ascent
was an important risk factor. AMS risk decreased by
19 per cent for each additional day spent between the
airstrip at Lukla (2804 m) and the place of survey,
Pheriche (4243 m).

18.6.2

Fluid intake

Trek leaders often urge their clients to drink plenty as

they gain altitude in order to avoid AMS. There
seems no good scientific reason for this advice.
Providing enough fluid is taken to avoid dehydration, further intake will only be excreted. However,
there is a recent epidemiological study that appears
to lend some support for this practice. Basnyat et al.
(1999) gave questionnaires to Everest Base Camp
trekkers at Pheriche (4243 m) and found that 30 per
cent of them had AMS. They asked about daily fluid
intake and found that the higher the intake (up to
5 L/day) the lower the incidence of AMS (odds ratio
1.54). But in the only controlled trial to address this
issue, Aoki and Robinson (1971) found that there
was no effect of hydration on AMS incidence. They
achieved dehydration by treatment of one group
with furosemide, and hyperhydration in another
with vasopressin; a third group was given a placebo.
All groups were decompressed at the same rate in a
chamber. Clearly more work is needed to answer this
question.

18.63

Drugs for prophylaxis

ACETAZOLAMIDE

Cain and Dunn (1965) were the first to show that

acetazolamide (Diamox) increases ventilation and

Pa02, and decreases Pac02. It has been shown to

reduce the incidence and severity of AMS in a
number of double-blind controlled trials in the field
(Forwand etal. 1968, Birmingham Medical Research
Group 1981, Larsen et al. 1982). All symptoms are
improved, as well as general performance, as judged
by peer review. Sleep was improved and the profound
desaturation associated with periodic breathing
(Chapter 13) was relieved (Sutton et al. 1979).
Acetazolamide has been shown to prevent patients
with asthma from developing AMS (Mirrakhimov et
al. 1993). In these trials, the dose was 250 mg orally
8 hourly, started 1 day before ascent, except in the
Birmingham trial where the dose was one 500 mg
slow release tablet daily. This dose, or 250 mg normal
release twice daily (which is cheaper), used to be the
recommended regimen. More recently many are
recommending half that dose morning and evening
since it is believed that protection is adequate and
side effects are fewer. However, although this may
well be true, there are as yet no trials to support this
recommendation. Treatment should be started
24-48 h before ascent to altitude.
The duration of treatment depends on the circumstance and situation. In many treks, the exposure to
conditions when AMS may be a problem is limited to
a few days and obviously treatment can be discontinued when the party has descended from altitude.
In situations where subjects go to altitude and stay
there, the risk of AMS is limited to the first 4-5 days
so that treatment could reasonably be stopped after
that.
However, a study by the Birmingham group
(Bradwell et al. 1986) has shown that taking acetazolamide for 3 weeks at 4846 m conferred a benefit in
that the group on treatment lost less weight, lost less
muscle bulk and had superior exercise performance
than those on placebo. Here the drug was being used
not so much to prevent AMS as to reduce altitude
deterioration.
The side effects of acetazolamide consist of a mild
diuresis and paresthesiae in the hands and feet,
which tend to dimmish with continued use of the
drug. A few people find this tingling very disturbing,
some are troubled by gastric side effects. Also, fizzy
drinks taste flat; this is due to the inhibition of
carbonic anhydrase in the tongue so that the conversion of carbon dioxide to carbonic acid fails to
take place in the time available as the drink passes
over the tongue, and the acid-sensing buds are not

228 Acute mountain sickness

stimulated. The safety of acetazolamide is assured by

its widespread use in glaucoma where it is used for
years at doses similar to that recommended for AMS
prophylaxis.
The ethics of the use of acetazolamide (or that of
any drug), especially if used throughout an
expedition, need consideration but in the end it is for
the individual or team to decide.
The mechanism of action of acetazolamide is
thought to be due to its inhibition of carbonic
anhydrase rather than its diuretic action. It is quite a
mild diuretic and more powerful diuretics are said to
be less effective though no direct comparisons have
been made in controlled trials. Interference with
carbon dioxide transport is thought to result in intracellular acidosis, including the cells of the medullary
chemoreceptor. In this way it acts as a respiratory
stimulant. It has been shown to shift the ventilatory
carbon dioxide response curve to the left, as happens
with acclimatization (section 5.12), although it does
not affect the slope. The acute effect after a single
dose results in a reduction in the hypoxic ventilatory
response, though with a few hours administration
this is restored (Swenson and Hughes 1993).
It probably also acts as a respiratory stimulant by
promoting the excretion of bicarbonate by the
kidneys, thus correcting the respiratory alkalosis due
to hypoxic-induced hyperventllation. In effect the
subject is given an artificial respiratory acclimatization. The importance of this renal effect is suggested
by Swenson et al. (1991) in a study in which the drug
benzolamide, a selective inhibitor of renal carbonic
anhydrase, reduced high altitude periodic breathing,
a feature of acetazolamide use. A recent trial of
benzolamide as a prophylactic for AMS (Collier et al.
1997a) showed it to be beneficial compared with
placebo, suggesting that inhibition of cerebral
carbonic anhydrase may not be the important action
of acetazolamide.
Another possible mechanism is via its effect on
cerebral blood flow (Vorstrup et al. 1984). Acetazolamide increases cerebral blood flow, which would
increase cerebral P02. However, increased PCo2'
which has the same effect on cerebral blood flow,
seems to increase the symptoms of AMS at the same
level of hypoxia (section 18.5.2). Additionally, the
dosage used in this study (1 g i.v.) was very large
compared with that used in AMS prophylaxis. Jensen
et al. (1990) found that, although 1.5 g acetazolamide
caused a 22 per cent increase in cerebral blood flow

after 2 h, there was no change in AMS symptoms.

Also Hackett et al. (1988a) found no change in
cerebral blood flow (as measured by transcranial
Doppler ultrasound) in subjects with or without
AMS after 0.25 g acetazolamide intravenously.
SPIRONOLACTONE

Jain et al. (1986) compared spironolactone with

acetazolamide and placebo. They found both drugs
to be effective in ameliorating AMS, with spironolactone being possibly superior. This confirms a
previous uncontrolled report (Currie etal. 1976).
DEXAMETHASONE AND ASPIRIN

Dexamethasone (4 mg 6 hourly) has been tried on

the grounds that it is effective in cerebral edema. In a
double-blind crossover chamber study it was found
to be an effective prophylactic (Johnson et al. 1984)
and was found to be superior when compared with
acetazolamide (Ellsworth et al. 1991). Rock et al.
(1989) carried out a dose ranging chamber experiment and concluded that 4 mg 12 hourly was the
minimum effective dose. The same group had
previously found that, if dexamethasone was given
for only 48 h after arrival at altitude, it was effective
in reducing symptoms, but that after stopping the
drug, symptoms of AMS began (Rock et al. 1989).
The combination of acetazolamide and dexamethasone has been shown to be more effective than
acetazolamide alone, especially in preventing the
cerebral symptoms of AMS (Bernhard et al. 1998).
Aspirin has been shown to be similarly effective as a
prophylactic (Burtscher et al. 1998) but, like dexamethasone, does not affect oxygen saturation. A later
study (Burtscher et al. 1999) found that aspirin alone
was not very effective in preventing the headache of
AMS in subjects skiing to a mountain hut, whereas
aspirin in combination with dexamethasone was.
There was no placebo arm in this trial.
NIFEDIPINE
Nifedipine has been shown to be beneficial for both
treatment and prophylaxis of HAPE (sections 19.3.1,
19.3.2) so Hohenhaus et al. (1994) carried out a
double-blind placebo-controlled trial of its use in
benign AMS. They found that, even though
pulmonary artery pressure was lower in the drug
group, there was no effect on AMS scores.

Treatment 229

OTHER DRUGS
Theophylline (300 mg) has been shown to be
beneficial as a prophylactic in a placebo-controlled
double-blind trial by Kuepper et al (1999). This
drug also reduces sleep disturbance and periodic
breathing.
Herbal extracts have been advocated both as
preventative and curative for AMS. As is usual in
herbal medicine there are few good trials to guide us.
However, some remedies have now been tested. An
extract of Ginko biloba (EGb 761) was studied by
Roncin et al. (1996) in a placebo-controlled trial and
found to be very effective as a prophylactic. Coca,
from the coca leaf, is very commonly taken in South
America either infused as a tea or chewed. Many
people are convinced of its efficacy in preventing
AMS but there seem to be no trials to confirm this.

18.7

TREATMENT

Most cases of AMS will get better in 24-48 h with no

treatment. If there is progression of symptoms to
those of acute pulmonary edema, or serious cerebral
edema, action is vital since these two disorders are
frequently fatal in a matter of hours. Their treatment
is discussed in Chapters 19 and 20 respectively.

18.7.1

Rest, acetazolamide

Rest alone often relieves the symptoms of AMS

(Bartsch et al. 1993), and this fact needs to be borne
in mind in trials of therapy in AMS. Acetazolamide
had been shown to be an effective treatment of AMS
as well as a prophylactic (Bradwell et al. 1988,
Grissom et al. 1992). The earlier study used a single
large dose (1.5 g) whereas the later study used the
more conventional 250 mg 8 hourly. Pa02 as well as
symptoms were improved.
Dexamethasone was shown, in a double-blind
trial, to be effective as an emergency treatment for
acute AMS (Ferrazzini et al. 1987). The dosage used
was 8 mg initially followed by 4 mg every 6 h. Levine
et al. (1989) also found it to be effective in relieving
AMS symptoms compared with placebo but it had
no effect on fluid shifts, oxygenation, sleep apnea,
urinary catecholamine levels, chest radiographs or
perfusion scans. These findings emphasize the

dictum that, in the event of HAPE or HACE,

patients should be taken to lower altitude as soon as
possible.

18.7.2 Aspirin, paracetamol,

nonsteroidal anti-inflammatory agents,
dexamethasone
For the headache of AMS, aspirin or paracetamol is
often used but there are no controlled trials and they
are often ineffective. A double-blind, placebocontrolled trial of ibuprofen (400 mg) showed it to
be more effective than placebo in relieving headache
(Broom et al. 1994). Keller et al. (1995) carried out a
trial comparing dexamethasone with hyperbaria (in
a Certec bag) for 1 h. Assessment 1 h after treatment
found hyperbaria to be better but at 11 h dexamethasone was more effective.

18.73

Other drugs

SUMATRIPTAN
The possibility that the headache in AMS and in
migraine might have a common mechanism stimulated a group from Heidelberg to carry out a placebocontrolled trial of sumatriptan, a 5HT antagonist
effective in migraine. Although the pooled results
failed to show significant benefit, analysis of male
and female subjects separately showed significant
benefit in men (Utiger et al. 1999).

18.7.4

Oxygen

Oxygen may help, but frequently does not, and its

use, besides being impractical in most cases, would
impede acclimatization. Voluntary hyperventilation
often helps and probably does promote acclimatization. Inhalation of 3 per cent carbon dioxide in air
has been claimed to alleviate symptoms in one study
(Harvey et al. 1988) but not in another (Bartsch et al.
1990). Both found a rise in Pa02, due presumably to
hyperventilation. In the latter study most subjects
given air to breathe had a reduction in symptoms,
indicating the importance of the placebo effect or
perhaps the beneficial effect of rest.
The place of portable inflatable pressure chambers
(the Gamowbag) is considered in Chapter 19.

230 Acute mountain sickness

Table 18.3 Lake Louise consensus: scoring ofAMS
(a) AMS self-assessment. The sum of the responses is the AMS self-report score. Headache and at least one other
symptom must be present for the diagnosis of AMS. A score of 3 or more is taken as AMS. It is suggested that this part of
the scoring system be always used and reported separately. The question relating to sleep will not always be relevant,
e.g. in short 1-day studies or in evening assessment when twice-daily scoring is used.

Headache

Gastrointestinal symptoms

Fatigue and/or weakness

Dizziness/light-headedness

Difficulty sleeping

0 None at all
1 Mild headache
2 Moderate headache
3 Severe headache, incapacitating
0 Good appetite
1 Poor appetite or nausea
2 Moderate nausea or vomiting
3 Severe, incapacitating nausea and vomiting
0 Not tired or weak
1 Mild fatigue/weakness
2 Moderate fatigue/weakness
3 Severe fatigue/weakness
0 None
1 Mild
2 Moderate
3 Severe, incapacitating
0 Slept as well as usual
1 Did not sleep as well as usual
2 Woke many times, poor night's sleep
3 Could not sleep at all

(b) Clinical assessment. This portion of the scoring system contains information gained by examination. The clinical
assessment score is the sum of scores in the following three questions.

Change in mental status

Ataxia (heel/toe walking)

Peripheral edema

0 No change
1 Lethargy/lassitude
2 Disorientated/confused
3 Stupor/semiconscious
4 Coma
0 None
1 Balancing maneuvers
2 Steps off the line
3 Falls down
4 Unable to stand
0 None
1 One location
2 Two or more locations

(c) Functional score. The functional consequences of the AMS self-reported score should be further evaluated by one
optional question asked after the AMS self-report questionnaire. Alternatively, this question may be asked by the
examiner if clinical assessment is performed.
Overall, if you had any of
these symptoms, how did
they affect your activities?

Source: after Roach et al. (1993).

0 Not at all
1 Mild reduction
2 Moderate reduction
3 Severe reduction (e.g. bed rest)

Scoring AMS symptoms 231

18.8

SCORING AMS SYMPTOMS

In studies on AMS there is obviously a need to score

the symptoms in some way and it is preferable for all
researchers to use the same system so that results of
different studies can be compared. The most complicated scoring system is the Environmental Symptom
Questionnaire (ESQ) (Sampson et al 1983). This
consists of 67 questions in its ESQ-III version, many
of which are overlapping and of uncertain relevance
to AMS. Most workers have used more simple
formats, scoring only three to five symptoms often
on a 0-3 scale, with 0 for no symptoms and 1, 2 and
3 for mild, moderate and severe symptoms. Either an
observer can administer the questionnaire to all
subjects or self-assessment by each subject can be
used; the two methods give similar results. A document was produced at the Lake Louise Hypoxia
Symposium in 1991, which, after defining AMS,
suggested a simple method of scoring along these
lines. This was modified at the next Hypoxia
Symposium in 1993 and is shown in Table 18.3
(Roach et al. 1993). It is important to note that one of
the modifications introduced was the caveat that
headache must be present for the diagnosis, as well as
at least one other of the symptoms listed. The
importance of insisting that headache is present for
the diagnosis is illustrated by a paper comparing a
previous system (Hackett's) with the Lake Louise
system (Roggla et al. 1996). It was found that the
Lake Louise system gave a spuriously high incidence,
25 per cent, compared with 8 per cent using the
Hackett system, at the moderate altitude of 2940 m.
Unfortunately the authors used the earlier 1991
version. Only 9 per cent of their subjects had
headache. Had they excluded from the diagnosis
subjects without headache, the two systems would
have given almost identical results.
There have been a number of studies comparing
the ESQ with the Lake Louise system. Bartsch et al.

(1993) did just this and found the percentages of

subjects diagnosed as having AMS in alpine huts at
four altitudes were comparable whichever system
was used. Maggiorini et al. (1998) applied questionnaires to 490 climbers in alpine huts up to 4559 m.
Using a Lake Louise score of 4 or more as the cutoff, they found a sensitivity of 78 per cent and
specificity of 93 per cent compared with the ESQ
AMS-C. Ellsworth et al. (1991) found similar results
in 400 climbers on Mount Rainier in Washington
State, USA. The Lake Louise system, being much
simpler, is therefore to be preferred.
There remains the question of the score at which
AMS is said to be present. On the self-report section,
five questions yield a possible top score of 15. The
consensus report suggests a score of 3 or more (with
headache) be deemed AMS, though from the study
quoted above a score of 4 or more seemed to give
better sensitivity and specificity. It is not clear what is
to be done with the other two parts of the assessment,
the clinical and functional scores, if they are used.
Clearly if these scores are added to the self-reported
scores a greater cut-off value would be appropriate.
Bartsch et al. (1993) suggested a figure of >5 for the
total Lake Louise score. We would suggest that, until
more data are available on the other parts of the
assessment, reliance be placed mainly on the selfreported score, which has been well validated.
These systems have all addressed the situation in
adults. The diagnosis of AMS in children presents
especial problems. Children too young to express
their symptoms verbally may be irritable, miserable
or tearful and refuse food. This behavior is even
more nonspecific than symptoms in adults. The only
safe course is to assume that this behavior in a child
who has gained altitude in the previous hours or days
indicates AMS until proved otherwise. Yaron et al.
(1998) have addressed the problem of scoring AMS
in preverbal children, and devised a 'fussiness' scale
derived from the Lake Louise system. For more
details of this see Chapter 28.

19
High altitude pulmonary edema
19.1
19.2

Introduction
Clinical presentation

19.3

Prevention

19.4

Treatment

232
233
237
238

SUMMARY
High altitude pulmonary edema (RAPE) is a potentially lethal form of acute mountain sickness (AMS)
which, like AMS, affects previously healthy people who
go rapidly to high altitude. A few hours after arrival the
patient suffers the usual symptoms of AMS but then
becomes more breathless than his companions. Over
the next few hours the breathlessness increases, and a
cough develops which is first dry but later productive
of frothy white sputum. The sputum may become
blood tinged. The signs of obvious pulmonary edema
are found and cyanosis may be detected. As the patient
literally drowns in his own secretions, he becomes
comatose and dies if no action is taken. Investigations
show raised pulse and respiratory rates, mild pyrexia
and leukocytosis and a characteristic radiographic
appearance. The pathology, in fatal cases, is of patchy
hemorrhagic edema of the lungs.
The most important management is to get the
patient down; if there is unavoidable delay, oxygen
and calcium channel blocking drugs are helpful.
Hyperbaric treatment in a Gamow (or Certec) bag
gives temporary relief and maybe useful in enabling a
patient to walk down rather than having to be carried.
The mechanism of the edema formation is not left
ventricular failure, as shown by normal wedge
pressures on cardiac catheterization. However, there
is severe pulmonary hypertension. There are a number of hypotheses about how this results in edema.

19.5

Outcome

19.6
19.7

Pathology
Mechanisms

240
241
241

The most favored mechanism is that the hypoxic

vasoconstriction is uneven, causing some areas to
have less and some more blood flow. The hyperperfused areas have raised capillary pressure and suffer stress failure of these vessels allowing proteins and
later blood cells to leak out into the interstitial space
and then alveolar spaces. There is also evidence of
inflammation; cytokines and arachidonic acid
metabolites are found in the edema fluid, and these
contribute to the vascular leakage. Exercise seems to
be a risk factor, presumably by raising the pulmonary
artery pressure.
Many patients who suffer HAPE show susceptibility to the condition on subsequent altitude exposure.
These subjects are found to have a brisk hypoxic
pressor response in their pulmonary circulation and
it is thought that this susceptibility may have a
genetic origin.

19.1

INTRODUCTION

There are a number of accounts of climbers dying of

'pneumonia' in early climbing literature. In retrospect it seems that many, if not most, of these fatalities were probably due to HAPE. One of the best
known was the death of Dr Jacottet on Mont Blanc in
1891. He died in the Vallot hut (4300 m) after taking
part in a rescue on the mountain. He spent 2 nights
in the hut with obvious symptoms of AMS, refusing

Clinical presentation 233

to go down. He died during the second night. The

autopsy showed 'acute edema of the lung' (oedeme
considerable) (Mosso 1898, p. 179).
In 1913, Ravenhill described what he called 'puna'
of the cardiac type as a lethal form or development of
AMS. Though he was wrong in attributing the condition to cardiac failure, his description of three cases
fits well with RAPE. However, his work was forgotten.
For the first half of the twentieth century the condition was uncommon in the European Alps because
few unacclimatized people spent nights above
2500 m, or in the Himalayas because approach
marches to the mountains were long enough for
acclimatization to take place. But in South America,
as Ravenhill's experience showed, railways had been
built and later roads to altitudes up to 3000 or
4000 m, thus putting large numbers of people at risk.
However, even in these countries the condition does
not seem to have been recognized for many years
after Ravenhill. West (1998, pp. 146-54) has
unearthed a description of a case reported by Alberto
Hurtado in 1937 in an obscure booklet. But the case
is atypical in a number of ways and Hurtado says (in
translation from the Spanish)
this is undoubtedly a type of Soroche (mountain
sickness) which is quite rare and infrequent and is
characterized by of intense congestion and edema
of the lung. Possibly in these cases there is a prior
cardiac condition ...

and this case did seem to have further long-term

problems suggestive of a cardiac condition. Although
this could be considered as the first case report of
HAPE after Ravenhill, there was mention of some
cases of soroche who had cough with frothy pink
sputum and who made a rapid recovery on descent
to low altitude. This was in an article by Harold
Crane, the chief surgeon of the hospital at the mining
town of Oroya (3750 m) in Peru. The article was
published in the Annals of the Faculty of Medicine,
Lima, in 1927. The first series of cases to be published
was by Leoncio Lizarraga Morla in 1955 in the same
journal. He mentioned that the condition was recognized by Carlos Monge M. as early as 1927. The seven
cases described were typical of HAPE and included
chest radiographs and electrocardiograms (ECGs)
typical of HAPE. This paper was followed by others,
including by Bardales, from Peru in the later 1950s.
The first reference in English to the condition we
now call HAPE was in a letter to the Journal of the

American Medical Association by Bardales in 1956. In

it he describes the condition briefly in high altitude
residents returning to altitude, saying it is particularly common in young people. For a fuller description of these papers and the full references, see West
(1998, pp. 146-54).
An interesting sidelight showing the situation in
the English-speaking world in the mid 1950s is given
by a letter to Dr Griffith Pugh which he published
with a comment in The Practitioner (Pugh 1955a). Dr
Pugh was the leading authority on altitude medicine
and physiology in the UK at the time. The letter gave
an excellent account of a fatal case of HAPE and
asked whether acute pulmonary edema is a common
symptom of high altitude sickness. Pugh, in his
response, indicates that he knew of no such case from
his experience or from the literature. The original letter and response together with a commentary are to
be found in West (1999b).
Herbert Hultgren visited Peru in 1959 and saw
cases of HAPE. He and his companion, Spickard,
wrote up their experiences in the Stanford Medical
Bulletin published in May 1960 under the title,
'Medical experiences in Peru'. In it they mention 41
cases of acute pulmonary edema in residents returning to altitude after a stay of 5-21 days at low altitude.
They correctly suggested that the mechanism was not
left ventricular failure but related to pulmonary
hypertension. Not surprisingly this important observation was not recognized at the time and so the condition was brought to the notice of the Englishspeaking medical world by Houston (1960) who
published his landmark paper on 'acute pulmonary
edema of high altitude' later in the same year in the
New England Journal of Medicine. Houston said 'this
single case is presented in the hope of stimulating
further reports' and 'pulmonary edema of high altitude deserves further study'. Both hope and declaration have been amply fulfilled in the succeeding years
by the description of hundreds of cases from all the
major mountainous areas and hundreds of studies
aimed at elucidating the mechanism of the condition
have been conducted, some of which will be reviewed
in this chapter.

19.2

CLINICAL PRESENTATION

HAPE, like AMS, affects previously healthy individuals on ascent to altitude. There is a wide range

234 High altitude pulmonary edema

of altitude of presentation of 2000-7000 m

(Lobenhoffer et al. 1982). A typical history is that the
subject ascends rapidly to altitude and is very active
getting there or on arrival. The subject suffers the
symptoms of AMS after arrival, though not necessarily very severely, and then becomes more short of
breath and lethargic and may have chest pain.
Physical signs are of tachycardia, tachypnea and
crackles at the lung bases. A dry cough develops,
which later progresses to one productive of frothy
white sputum and eventually blood tinged sputum.
Over a few hours the condition progresses with
increasing respiratory distress, orthopnea, cyanosis,
bubbling respirations, coma and death.

19.2.1

Case histories

CASE 1 (HOUSTON 1960)

A male patient left sea level on 18 June, reaching

16 700 ft (5090 m) by car and on foot 5 days later. He
had no symptoms until 1 day later when he noted
dyspnea progressing to severe orthopnea. Within a
few hours his breathing became progressively more
congested and labored. He sounded as though he was
literally drowning in his own fluid with an almost
continuous loud bubbling sound as if breathing
through liquid. A white froth resembling cotton
candy appeared to well up out of his mouth, which
was open. This was even though he was sitting up
with his head tilted back. The patient died within 8 h
of the onset of symptoms.
CASE 2

A Sherpa on a large expedition had carried a load

from 6400 m to 7000 m and returned. The following
morning he complained of severe headache and
malaise. He was anorexic and remained in his sleeping bag. On examination at mid-morning he was
found to be breathless on the slightest exertion,
cyanosed and had a dry cough. The pulse and respiratory rate were increased. Fine crackles were heard
at the lung bases. At noon he started down for a
lower camp at 5800 m accompanied by two expedition members. It was at once apparent that he could
not carry even a light load. Every 100-200 yards
(90-180 m) he had to stop, even though the route
was over an easy downhill glacier. He began coughing frothy white sputum, which later became blood

tinged. At about 100 m above the camp he was given

oxygen and was able to complete the journey without
stopping. After breathing oxygen for about 3 h at the
camp he declared himself well and refused any more
oxygen. He descended unaided to a lower camp next
day, carrying a load.

19.2.2

Incidence

It is difficult to obtain data on incidence of HAPE

because of the problem of knowing the number of
people at risk. As with AMS it will depend upon the
rate of ascent and the height reached. Hackett and
Rennie (1976) saw seven cases in 278 trekkers who
passed through Pheriche (4243 m) on their way to
Everest Base Camp, giving an incidence of 2.5 per
cent. The incidence of AMS in the same group was
53 per cent. Menon (1965) found an incidence of
0.57 per cent in Indian troops flown to the modest
altitude of Leh (3500 m). Hultgren and Marticorena
(1978) gave an incidence of 0.6 per cent in adults
going to La Oroya (3750 m) in Peru. In these series a
diagnosis was only made in clear, overt cases. If the
chests of all newcomers to altitude are auscultated,
crackles will be heard in many who would not be otherwise diagnosed as having HAPE, and radiographic
signs are also found on chest radiography in many
subjects. Hence we now believe that a degree of subclinical edema is probably present commonly in subjects with simple AMS and contributes to the
reduced 5a02 found at this time (section 18.4.8).
However, in simple AMS the edema is self-limiting
whereas in HAPE it is progressive.
The incidence will be affected by health education
of people going to altitude. It is the impression of
health workers at the aid post at Pheriche (4243 m)
in Nepal that the incidence is less following some
years of publicity about the dangers of HAPE
amongst trekkers and the trekking agencies.

19.2.3

Symptoms of HAPE

Table 19.1 shows the symptoms from the largest

series managed by a single physician, that of Menon
(1965), who reported 101 cases. The frequency of
chest pain, second only to breathlessness, is unusually high. Only 21 per cent of patients complained of

Clinical presentation 235

Table 19.1 HAPE: symptoms in 101 cases

Breathlessness
Chest pain
Headache
Nocturnal dyspnea
Dry cough
Haemoptysis
Nausea
Insomnia
Dizziness

84
66
63
59
51
39
26
23
18

Source: after Menon (1965).

chest pain in a German series (Lobenhoffer et al.

1982). Hallucinations are not uncommon and, with
confusion and irrational behavior, may make management difficult. Nocturnal dyspnea and the symptoms of AMS - headache, nausea and insomnia - are
all common.

19.2.4

Signs

The signs depend upon the stage of the condition.

Probably the earliest sign is of crackles at the lung
bases. These may be heard in subjects with no other
signs of HAPE and who do not progress to the full
blown condition. The presence of early edema may
be the cause of dry cough on exertion and of the shift
to the left of the pressure/volume curve of the lung
(Mansell et al. 1980, Gautier et al. 1982) and the
reduction in forced vital capacity (Welsh et al. 1993).
The pulse rate increases early and was over 120 in 70
of 101 patients in Menon's series (1965). The respiratory rate was over 30 in 69 cases; cyanosis was
detected in 52 subjects. The pulmonary artery pressure is high in this condition (section 19.2.7) giving
the signs of right ventricular heave and accentuated
pulmonary second sound in about half the patients.
Signs of right ventricular failure are not prominent
but 15 of Menon's patients had raised jugular venous
pressure and dependent edema is found in a number
of cases. The temperature is normal in at least 25 per
cent of cases but was found to be mildly elevated
(37-39 C) in 70 per cent of Menon's cases. In only
two cases was it above 39 C. Maggiorini et al. (1997)
found temperature to be elevated by a mean of

0.8 C compared with climbers without HAPE. The

systemic blood pressure is either normal or mildly
elevated (systolic 130-140 mmHg) as is found in
some subjects on ascent to altitude who do not have
HAPE.
Some subjects (15 in Menon's series) have mental
confusion and amnesia following recovery. This may
be due to hypoxia or cerebral edema (Chapter 20).

19.2.5

Radiology

Figure 19.1 shows a chest radiograph of a patient

with HAPE and a second radiograph 4 days later
after treatment. The typical features are of cottonwool blotches irregularly positioned in both lung
fields. They are frequently asymmetrical, possibly
being denser on the side which has been dependent. Very often, the right side is more densely
shadowed (Menon 1965). Quite frequently, the
lower zones, especially the costophrenic angles, are
spared as well as the apices. The pulmonary vessels
may be seen to be engorged (Marticorena et al.
1964). The radiographic appearance in early cases
shows more pathology than would be expected
from clinical examination (Menon 1965). In
patients with a second attack of HAPE there is no
consistent pattern in the areas of lung involved.
This patchy distribution of edema is even more
dramatically shown in computerized tomographic
scanning of the chest.
In treated cases the radiographic lesions clear rapidly
(see Figure 19.1), often within 2 days (Houston 1960),
though usually lagging behind symptoms.

19.2.6

Investigations

ELECTROCARDIOGRAPHY

The EGG shows tachycardia. The P waves are often

peaked (P pulmonale) and there is right axis deviation of the AQRS (mean +123). Some patients
show elevation of the S-T segment (Marticorena et
al. 1964). T-waves maybe inverted in the precordial
leads but this may be seen in asymptomatic subjects
at altitude (Milledge 1963). The EGG appearances
can be attributed to the very high pulmonary artery
pressure and the consequent increase in right ventricular work.

236 High altitude pulmonary edema

Image Not Available

Figure 19.1 Radiograph of a patient with high altitude pulmonary edema: (a) on admission and (b) 4 days later. (Reproduced with
permission of Dr T. Norboo ofLeh, Jammu and Kashmir, India.)

HEMATOLOGY

Menon (1965) found that hemoglobin concentration

was 14.0-16.0 g dlr1 and the sedimentation rate was
normal. The white cell count was raised in 75 of
95 cases. This elevation was due to an increase in
neutrophil count.
BLOOD GASES

P02 and arterial oxygen saturation are low compared

with normal values for that altitude. PC02 is very variable and is not significantly different from controls
(Antezana et al. 1982, Schoene etal. 1985).
URINE
Proteinuria was present in 4 of 101 cases (Menon
1965), but using more sensitive tests there was an
increase in urine protein in all subjects during the
first few days at altitude, the degree of proteinuria
correlating with the severity of AMS (Pines 1978;
Chapter 15).

19*2.7

Cardiac catheter studies

There have been a number of catheter studies carried

out on patients with RAPE before treatment
(Penaloza and Sime 1969, Antezana et al. 1982) or
soon after starting treatment (Fred et al. 1962,
Hultgren et al. 1964, Roy et al. 1969). In all these
studies there was found to be a high pulmonary
artery pressure compared with healthy subjects at the
same altitude (Table 19.2). The wedge pressures were
normal. The pulmonary artery pressure ranged up to
144 mm Hg systolic (Hultgren et al. 1964) and is usually 60-80 mmHg (Table 19.2). The normal wedge
pressure implies normal pulmonary venous and left
atrial pressures; in one subject direct measurement of
left atrial pressure was made via a patent foramen
ovale and was normal (Fred et al. 1962). The cardiac
output was within the normal range so the calculated
pulmonary resistance was markedly raised. There
was no evidence of left ventricular failure. Breathing
100 per cent oxygen resulted in a fall of pulmonary
artery pressure to normal values within 3 min in two

Prevention 237

Table 19.2 Cardiac catheter studies in HAPE

HAPE
Controls

5
50

81
29

5
9

49
13

5.8
6.4

Source: data from Antezana etal. (1982).

of five subjects. However, in the other three, pressures fell but leveled out at 40-50 mm Hg pulmonary
artery pressure, well above the upper limit of normal
at that altitude (Antezana et al. 1982).

19*2*8

Etiology and susceptibility

The etiology of HAPE is similar to that of AMS (section 18.4), all ages and both sexes being susceptible.
There is an impression that children and young
adults are more prone to HAPE than older people. It
seems that individual susceptibility is more clear cut
than for AMS; that is, subjects who have suffered
HAPE on one occasion are very likely to have problems on subsequent altitude trips.
Susceptible subjects are found to have a greater pulmonary pressor response to hypoxia than control
subjects who have been to altitude previously without
problems (Hultgren et al. 1971, Vachiery et al. 1995,
Eldridge etal. 1996, Scherrer etal. 1996). Hohenhaus
et al. (1995) studied both the pulmonary pressor and
hypoxic ventilatory responses in HAPE-susceptible
subjects and concluded that they had lower hypoxic
ventilatory response (HVR) than controls but not significantly different from subjects who had simple
AMS. The latter had a wide range of HVR. Some
HAPE-susceptible subjects had very brisk pressor
responses but not all subjects could be separated from
controls by this test. One possibility is that HAPE-susceptible individuals have a restricted lung vasculature
or just smaller lungs. A study by Steinacker et al.
(1998) tested this idea by comparing eight such subjects with controls at rest and on exercise in normoxia
and hypoxia. The HAPE-prone group had 35 per cent
smaller functional residual capacity and 7-10 per cent
smaller vital and total lung capacities, and did not
increase their diffusing capacities as much on exercise
under hypoxia. This lends support to the hypothesis

of smaller lungs in HAPE-susceptible individuals. A

similar conclusion had been reached by Podolsky et
al. (1996) who studied the pulmonary response to
exercise in HAPE-susceptible subjects at sea level and
3810 m. They found greater vascular reactivity in
HAPE subjects. The reactivity was not affected by
altitude or oxygenation so was due to either flowdependent pulmonary vasoconstriction or a reduced
vascular cross-sectional area. Duplain et al. (1999a)
measured sympathetic activity directly from postganglionic nerve discharge in HAPE-susceptible subjects
in response to a short hypoxic test. They found at both
high and low altitude that the test subjects had two to
three times the response compared with controls,
suggesting that sympathetic overactivation may be a
part of susceptibility.
In HAPE subjects, Hanoka et al. (1998) found an
association with certain HLA complexes (HLA-DR6
and HLA-DQ4). Morrell et al. (1999) reported that
Khirghiz highlanders with pulmonary hypertension
had a high incidence of the D allele of the ACE gene
compared with subjects suspected but found not to
have pulmonary hypertension. These studies support
the idea that HAPE susceptibility has a genetic basis.

193
19.3.1

PREVENTION
Slow ascent

It is generally considered that HAPE is a progression

or complication of benign AMS. Therefore, if precautions are taken to prevent AMS by making a sufficiently slow ascent (section 18.6.1), HAPE will also
be prevented. However, people often have to ascend
at a rate that puts them at risk of AMS and, of course,
the great majority of patients who suffer from benign
AMS do not progress to the malignant forms.

238 High altitude pulmonary edema

193.2

Exercise

Many case histories from Houston (1960) onwards

emphasize the point that patients have been very energetic while getting to high altitude or on arrival there.
Ravenhill (1913) was of the opinion that physical exertion rendered a man more susceptible to AMS in general. The Indian Army, with great experience of HAPE
since the war with China in the Himalayas in 1962,
advises all inductees to altitude to take no unnecessary
exertion for the first 72 h. Exercise, by increasing
cardiac output, raises the pulmonary artery pressure,
especially in subjects susceptible to HAPE, and it is
believed that the higher the pulmonary artery pressure, the greater the risk of HAPE. In healthy subjects
at altitude, Eldridge et al. (1998) have shown that
strenuous exercise results in the appearance of red
cells, white cells and y8T cells in the lavage fluid. The
latter cells indicate damage to the endothelium and
play a role in inflammation. Anholm et al. (1999)
found radiographic evidence of pulmonary edema in a
group of cyclists at the end of a run at modest altitude.
However, HAPE can occur in the absence of hard
physical exertion; 66 of Menon's 101 cases had taken
no exercise more strenuous than office work, traveling
as a passenger in a truck or walking about on level
ground (Menon 1965). Nevertheless, the anecdotal
evidence is strong enough to advise people who have
to make a rapid ascent to altitude to avoid hard physical exertion for 2-3 days.

1933

Drugs

Acetazolamide (section 18.6.2), by preventing or at

least reducing AMS, probably also reduces the risk of
HAPE. Nifedipine has been shown in a controlled
trial to reduce the risk of HAPE in susceptible subjects (Bartsch etal. 1991b).

19.4
19.4.1

TREATMENT
Descent

The single most important maneuver in treating a

case of HAPE is to get the patient down as fast and
as far as possible. Even a descent of as little as
300 m may improve a patient's condition dramatically (report of case 2 in section 19.2). However,

there are often unavoidable delays while awaiting

evacuation and there are a number of therapeutic
possibilities.

19.4.2

Oxygen

Breathing air enriched with oxygen, if available, is an

obvious treatment. It relieves hypoxia and reduces
pulmonary artery pressure (section 19.2.6), but,
although most patients benefit, in some the relief is
only partial and in a few deterioration may continue,
perhaps because of inefficiencies in the delivery
system. The dosage of oxygen is usually dictated by
its supply. If there is sufficient, a flow of 6-10 L mnr1
is indicated for the first few hours, reducing to
2-4 L min"1 when there is improvement.

19.43

Diuretics

Since the patient has edema, diuretics have been used

in the treatment of HAPE (Singh et al. 1965).
However, physicians who see a lot of the condition
now do not advocate their use.

19.4.4 Antibiotics
Antibiotics by themselves will not cure HAPE.
However, many cases have mild fever and leukocytosis suggesting that infection may play a part.
Therefore, it would seem prudent to add a broad
spectrum antibiotic to the treatment regimen,
although Menon (1965) discontinued their use in his
last 44 cases with no apparent disadvantage.

19.4.5

Calcium channel blockers

Oelz et al. (1989) showed that nifedipine was of value

in the treatment of HAPE. Six subjects with clinical
physiological and radiographic evidence of HAPE
were treated with 10 mg of nifedipine sublingually
and 20 mg slow release orally 6 hourly thereafter.
Despite continued exercise at 4559 m this treatment
without oxygen resulted in clinical improvement,
better oxygenation, reduced (A-a)P02 gradient and
pulmonary artery pressure, and clearing of alveolar
edema. The sublingual preparation is very rapidly
absorbed and occasionally results in systemic
hypotension; most physicians now do not use it.

Treatment 239

19.4.6

Nitric oxide

Nitric oxide produced by endothelial cells is a naturally occurring potent vasodilator. It was first used in
the treatment of HAPE by Scherrer etal (1996), who
took 18 HAPE-susceptible subjects to 4559 m. Their
pulmonary artery pressures were higher and Pa02
lower than control, nonsusceptible subjects. Nitric
oxide lowered their pulmonary artery pressure and
raised their Pa02 whereas in control subjects Pa02 fell.
The latter was thought to be due to increasing ventilation/perfusion mismatching. In HAPE subjects,
nitric oxide goes preferentially to ventilated, nonedematous areas dilating the vessels there. This shifts
blood flow from edematous to nonedematous areas
with improvement in V/Q matching. The beneficial
effects of nitric oxide were confirmed by Anand et al.
(1998) in 14 patients with established HAPE. They
compared nitric oxide treatment with 50 per cent
oxygen and nitric oxide plus 50 per cent oxygen.
Both nitric oxide and oxygen were effective in reducing pulmonary artery pressure and improving Pa02
but the combination had an additive effect. These
studies are of great interest in understanding the
mechanisms of HAPE, but nitric oxide is not suitable
for use in the field and if the patient reaches a hospital the descent, calcium channel blockers and oxygen
are almost always effective in relieving the condition.

19.4.7

Other vasodilators

Hackett et al. (1992) have shown that several

vasodilators are beneficial in HAPE as indicated by a
reduction in pulmonary artery pressure, pulmonary
vascular resistance and improved gas exchange
(Figure 19.2). Nifedipine and hydralazine were of
equal benefit but rather less effective than oxygen.
Phentolamine, an alpha-blocker, was more effective
than oxygen and, when combined with oxygen, was
even more effective.

19.4.8

Other drugs

Digoxin has been used. Menon (1965) observed the

effect of an intravenous dose of 0.5-1.5 mg in 66
patients and claimed that the response was uniformly
good within a few hours, even in patients given only
1 L min'1 of added oxygen. However, there was no
evidence of myocardial failure nor was there atrial
fibrillation - the current indications for digoxin therapy - and its use is no longer advised.
Morphine (15-30 mg i.v.) has been used, again
with the clinical impression that this resulted in a
reduction in pulmonary edema. As it does in acute
left ventricular failure, it also makes the patient more
comfortable, possibly by causing peripheral vasodilatation and a shift of blood from central to
peripheral circulations. However, its respiratory
depressant effects should make for caution in its use.
Corticosteroids have been used in a few cases with
no clear result but the beneficial effect of dexamethasone in simple AMS shown in a controlled trial by
Ferrazzini etal. (1987) would justify its use in HAPE,
especially in severe cases where there is often an element of HACE as well.

19.4.9 Expiratory positive airways

pressure

Figure 19.2 Percentage change in mean pulmonary artery

pressure (P pa) and pulmonary vascular resistance (PVR) with five
different interventions in subjects with HAPE. Nif, nifedipine;
Hydral, hydralazine; Phen, phentolamine. (Reproduced with
permission from Hackettei a I. 1992.)

Feldman and Herndon (1977) suggested that expiratory positive airways pressure might be beneficial in
HAPE by analogy with its use in other forms of pulmonary edema. They proposed a simple device in
which the subject exhaled through an underwater
tube to achieve the desired positive pressure while
inspiration was direct from atmosphere.

240 High altitude pulmonary edema

Schoene et al. (1985) used a commercial expiratory positive pressure mask on four patients with
HAPE on Mount McKinley in Alaska. They showed
that, using the mask, arterial saturation was
increased with increasing positive pressure (up to
10 cmH 2 O). There was a concomitant rise in PC02
but not of heart rate. The intrathoracic pressure
would be negative during inspiration so the cardiac
output would probably not be reduced. A similar
effect can be achieved by pursed lips expiration as
used by patients with severe emphysema; mountain
guides advise this, presumably because they have
found it to be beneficial.

19.4*10 Portable hyperbaric chamber:

the Gamow or Certec bags
A lightweight rubberized canvas bag has been developed into which a patient can be zipped and the bag
pressurized using a foot pump. There is a pressure
relief valve set to 2 psi (100 mmHg). This pressure
gives the equivalent altitude reduction of almost
2000 m from a typical base camp altitude of
4000-5000 m. There are currently two commercially
available bags, the Gamow from the USA and Certec
from France. There have been numerous accounts
of their use in HAPE and RACE, with good results
(Robertson and Shlim 1991). One report draws
attention to the considerable placebo effect of the
procedure. Roach and Hackett (1993) have reviewed
the efficacy of hyperbaric treatment. They conclude
that both oxygen and hyperbaria are effective. There
may be a rebound effect some hours after treatment
(typically 1-2 h duration). A recent controlled trial
in benign AMS has shown that 1 h in the bag at
pressure (193 mbar, equivalent to 147 mm Hg) was
significantly more effective in reducing symptoms
than control (1 h at the trivial pressure of 20 mbar,
equivalent to 15 mmHg) (Bartsch et al. 1993). The
effort of maintaining the necessary pumping for
even 1 h is considerable, especially at altitude and if
the number of rescuers is limited. Duff (1999),
reporting a case, makes the useful point that some
patients with severe HAPE or HACE may be
orthopneic when made to lie flat in a compression
bag and in their confused state may become belligerent. Their condition may be confused with
claustrophobia. The solution is to position the bag
at a 30 head-up angle.

19.4*11

Summary of treatment

The treatment of HAPE is:

Get the patient down in altitude as fast and as low
as possible.
While awaiting evacuation, or if evacuation is not
possible, give oxygen or hyperbaria. Nifedipine
20 mg slow release (or possibly phentolamine)
should be given and a broad spectrum antibiotic
should be considered. If there is any suspicion of
cerebral edema as well give dexamethasone 4 mg
(Chapter 20).
The use of expiratory positive airways pressure,
with a respiratory valve device or, failing that, by
pursed lips breathing, will give some temporary
improvement.

19.5

OUTCOME

In fully established cases, where evacuation to

lower altitude is impossible, death within a few
hours is usual. If cases are recognized early and
taken down, patients usually recover completely in
1-2 days but occasionally they continue to deteriorate and die even after being brought down to
lower altitude, especially if there are symptoms of
cerebral edema (Dickinson et al. 1983). Only one
case has been reported as progressing to adult respiratory distress syndrome (Zimmerman and
Crapo 1980). Usually the pulmonary hypertension
reduces rapidly on going to low altitude and the
inverted T-waves on the EGG return to normal
(Singh et al. 1965, Figure 3). But Menon (1965)
mentions two soldiers (out of 101 cases) who having recovered from HAPE had to be evacuated later
because of breathlessness, precordial pain and
inverted T-waves in their EGG, and Fiorenzano et
al. (1997) recently reported one case with prolonged T-wave inversion in the precordial leads
suggesting prolonged pulmonary hypertension.
Even patients who have apparently fully recovered
have been shown to have significant hypoxemia
and widened (A-a)P02 gradients for up to 12 weeks
(Guleria et al 1969). However, after recovery at
lower altitudes, many climbers have returned to
climb their peaks without further trouble.

Mechanisms 241

19,6

19*6*1

PATHOLOGY

Postmortem examination

There have been a number of postmortem studies

which have shown a similar pathology in the heart and
lungs (Hultgren et al 1962, Arias-Stella and Kruger
1963, Marticorena et al. 1964, Nayak etal. 1964, Singh
et al. 1965, Dickinson etal. 1983). The lungs are heavy
and feel solid. The cut surface weeps edema fluid,
usually blood stained, but a striking feature is the
nonuniform nature of the edema. Areas of hemorrhagic edema alternate with clear edema and with
areas which are virtually normal (or overinflated).
Pulmonary arterial thrombi are commonly found.
On microscopy, alveoli are filled with fluid containing red blood cells, polymorphs and macrophages, though not in great numbers. Hyaline
membranes are found in the alveoli, identical with
those seen in respiratory distress syndrome of the
newborn. The pulmonary capillaries are congested
with small arteries and veins containing thrombi and
fibrin clot. Perivascular edema and hemorrhage are
found. In postmortem studies of high altitude
natives from South America the pulmonary arteries
are very muscular and the right ventricle is hypertrophied. In lowlanders the pulmonary vessels have
normal musculature (Dickinson etal. 1983).

19*6.2

The edema fluid

The hyaline membranes are probably formed by coalescence of proteins, suggesting a high protein edema.
It has been shown in life that the edema fluid is rich in
protein. Hackett et al. (1986) sampled pure edema
fluid by bronchoscopy in one case and showed it to
have a plasma/fluid ratio of 0. 8:1.1 for total protein.
Schoene et al. (1986) took bronchoalveolar lavage
(BAL) fluid from three cases of RAPE and compared
it with lavage fluid from three controls at the same
altitude (4400 m). The fluid from patients was rich in
high molecular weight protein, red cells and
macrophages. These findings suggest a 'large pore'
leak type of edema. In further studies the same group
(Schoene et al. 1988) also found that the fluid was rich
in alveolar macrophages. There was evidence of activation of complement (C5a) and release of thromboxane B2 and leukotriene B4. Tsukimoto et al. (1994)
also showed, under tightly controlled laboratory con-

ditions in the rat, that elevation of the capillary pressure alone resulted in the appearance of leukotriene
B4 in the BAL fluid. Recently a Japanese group (Kubo
et al. 1998) has carried out BAL in seven patients with
early HAPE and found increased cell counts of
macrophages, lymphocytes and neutrophils plus
markedly elevated concentrations of proteins, lactate
dehydrogenase, IL-lp, IL-6, IL-8 and TNF-Ot. IL-6
and TNF-oc were shown to correlate with the Pa02 and
pulmonary artery driving pressure (PPA - -Pwedge)-

19*7

MECHANISMS

HAPE develops from AMS and the mechanisms that

cause the symptoms of AMS (section 18.5) are
already operating in these patients. Indeed, there is
evidence suggesting that a degree of subclinical pulmonary edema is common during the second and
third days at altitude. That is, there is a reduction in
vital capacity, a shift of the pressure/volume curve of
the lung (Mansell etal. 1980, Gautier etal. 1982) and
an increase in alveolar arterial oxygen difference
(Sutton et al. 1976). This might simply be part of a
generalized increase in extracellular fluid (ECF) volume which shows itself as subcutaneous edema in
the fa'ce on rising and in the ankles later in the day.
In the skull, the same edema raises the intracellular
pressure and gives rise to the symptoms of AMS, but
the progression from this mild edema to clinical
pulmonary edema requires a further mechanism or
mechanisms.

19*7*1

Facts to be explained

Any hypothesis that seeks to explain the mechanism

of HAPE must take into account the following facts:
The edema is of the high protein type.
The patchy distribution of the edema seen on
postmortem and radiology (Figure 19.1).
The very high pulmonary artery pressure and normal wedge (and left atrial) pressures (Table 19.2);
the improvement which follows treatment with
different drugs which reduce the pulmonary
artery pressure indicates the importance of this
factor in the mechanism of HAPE.
The presence of vascular thrombi and fibrin clots
in pulmonary vessels (section 19.4.1).

242 High altitude pulmonary edema

The individual susceptibility which is associated

with an increased hypoxic pulmonary pressor
response (Hultgren et al. 1971) and response to
exercise (Kawashima et al. 1989).
The increased risk of RAPE with exercise on
arrival at altitude.

19.7*2

Left ventricular failure

Although RAPE resembles left ventricular failure

(LVF) clinically, which is why Ravenhill (1913) called
it puna of the cardiac type, it is not now thought to be
due to heart failure. Catheter studies have shown
normal wedge pressures and the edema fluid is of the
high protein permeability type. Also the chest radiograph and pathology are not typical of LVF.

19.73

Pulmonary hypertension

The extraordinarily high pulmonary artery pressure

found in RAPE must play a role in the mechanism of
the condition. High pulmonary artery pressure by
itself does not cause edema, as for instance in primary pulmonary hypertension, or in a group of men
studied by Sartori and colleagues (1999). These individuals had suffered an episode of hypoxia in the
neonatal period and as a result had exaggerated pulmonary hypoxic pressor responses. When taken up
to high altitude they had high pulmonary artery pressures but did not get RAPE. This is perhaps not
surprising since the resistance vessels, the arterioles,
are upstream of capillaries and therefore capillary
pressure should be normal. One must therefore
postulate some further mechanism as well as, but
related to, the pulmonary hypertension. The following have been proposed.

19.7.4 Uneven pulmonary

vasoconstriction and perfusion
Hultgren (1969) suggested that the edema is caused
by a very powerful, but uneven, vasoconstriction so
that there is reduced blood flow in some parts of the
lung and torrential blood flow in others. He showed
(Hultgren et al. 1966) that if one progressively ties off
more and more of the pulmonary arterial tree in a
dog, thus forcing the total cardiac output through
only a portion of the lung, pulmonary edema results
in the part of the lung that remains perfused.

A case report by Dombret et al. (1987) provides

confirmation in humans of Hultgren's experimental
findings. The reported patient had a massive pulmonary embolus resulting in perfusion being
reduced to only the left upper and middle lobes. She
developed symptoms and signs of pulmonary edema,
which on radiograph were shown to be confined to
those same perfused lobes.
Evidence in favor of this mechanism as being the
cause of HAPE is provided by Viswanathan et al.
(1979) who, at sea level, studied 12 subjects who had
recovered from HAPE. They showed that, on being
given 10 per cent oxygen to breathe, they had a greater
pulmonary pressor response than controls and on
lung scanning their perfusion was more uneven.
This hypothesis accounts well for the patchy distribution of the condition. High flow through less
severely constricted areas might well produce edema
by capillary stress failure (section 19.7.5). Added support for this hypothesis came from a paper by Hackett
et al. (1980a), who collected four cases of HAPE
occurring at very modest altitudes (2000-3000 m) in
subjects who had a congenital absence of the right
pulmonary artery. The edema developed in the left
lung, which received the total cardiac output. That
four cases of HAPE developed in such an uncommon
condition (only 50 cases have been described in the
world literature) strongly suggests a causative rather
than a coincidental association.

19.7.5 Stress failure of pulmonary

capillaries
It has been proposed that HAPE is caused by damage
to the walls of pulmonary capillaries as a result of
very high wall stresses associated with increased capillary transmural pressure (West et al. 1991, West
and Mathieu-Costello 1992a). These high capillary
pressures are the result of uneven hypoxic pulmonary vasoconstriction as originally proposed by
Hultgren (1969). Extensive laboratory studies have
now shown that raising capillary transmural pressure
causes ultrastructural damage to the capillary walls,
including disruption of the capillary endothelial
layer, alveolar epithelial layer, and sometimes, all layers of the wall (West et al. 1991, Tsukimoto et al.
1991, Costello et al. 1992, Elliott et al. 1992, Fu et al.
1992). The result is a high permeability form of pulmonary edema (Tsukimoto et al. 1994). Figure 19.3

Mechanisms 243

Figure 19.3 Electron micrograph of a pulmonary capillary in a

rat exposed to a barometric pressure of 294 mm Hgfor 4 h. Note
rupture of the capillary wall with a red cell moving out of the
capillary lumen (c) into an alveolus (a). (From West et al. 1995.)

is an electron micrograph showing rupture of a pulmonary capillary wall in a rat exposed to a barometric pressure of 294 mm Hg for 4 h. Note the red
cell in the process of moving from the capillary
lumen to the alveolar space (West et al. 1995).
The work on stress failure began because of two
key observations about RAPE. The first is that, as
described above, there is a very strong relationship

between the occurrence of RAPE and the height of

the pulmonary arterial pressure. This suggests that
RAPE is caused in some way by high vascular pressures in the pulmonary circulation. The second
observation was that samples of alveolar fluid
obtained by bronchoalveolar lavage in patients with
RAPE show that the fluid is of the high permeability
type with a large concentration of high molecular
weight proteins and many cells. This observation
strongly suggests that RAPE is associated with damage to the walls of the pulmonary capillaries by
some mechanism. The problem therefore was to
reconcile a hydrostatic pressure basis for the disease
with the development of abnormalities in the
capillary walls. As a result, extensive studies of the
effects of raising pulmonary capillary pressure on
the ultrastructure of pulmonary capillaries were
carried out. These showed that stress failure is common in rabbit lung when the capillary transmural
pressure rises to 40 mm Hg and that when it occurs
it causes a high permeability type of pulmonary
edema.
It is not at all surprising that pulmonary capillaries
break under these conditions because the calculated
wall stress of the capillary is extremely high (West et
al. 1991, West and Matthieu-Costello 1992b). The
surprising thing is not that the capillaries fail, but
that they do not fail more often. Stress failure is now
believed to play a role in a number of lung diseases
(West and Mathieu-Costello 1992c) and is also the

Figure 19.4 Diagram summarizing the pathogenesis of HAPE based on stress failure of pulmonary capillaries.
PA, pulmonary artery. (From West and Mathieu-Costello 1992a.)

244 High altitude pulmonary edema

cause of bleeding into the lungs of racehorses, which

is extremely common (West et al. 1993).
Bronchoalveolar lavage studies in patients with
RAPE show the presence of inflammatory markers
including leukotriene B4, other lipoxygenase products
of arachidonic acid metabolism, and C5a complement
in the lavage fluid (Schoene et al. 1988). At first sight
these findings might seem to argue against stress failure
of pulmonary capillaries as a mechanism. However, an
important feature of the ultrastructural changes in
stress failure is that the basement membranes of
capillary endothelial cells are frequently exposed
(Tsukimoto et al. 1991). The exposed basement membrane is electrically charged and highly reactive, and
can be expected to activate leucocytes and platelets. In
bronchoalveolar studies of the rabbit preparation,
leukotriene B4 is seen in the lavage fluid (Tsukimoto et
al. 1994). Platelet activation will result in the formation
of fibrin thrombi, which are a feature of the pathology
of HAPE (Arias-Stella and Kruger 1963). Figure 19.4
summarizes the mechanism of HAPE.
A striking feature of stress failure of pulmonary
capillaries is that some of the breaks are rapidly
reversible when the pressure is reduced. In one study
carried out in rabbit lung, it was found that about
70 per cent of both the epithelial and endothelial
breaks closed within a few minutes of the pressure
being reduced (Elliott et al. 1992). This rapid
reversibility of most of the disruptions may explain
why patients with HAPE often quickly improve when
they descend to a lower altitude.
Stress failure of pulmonary capillaries had not previously been suggested as the mechanism of HAPE.
However, Mooi and co-workers (1978) studied the
ultrastructural changes that occurred in rat lungs
when the animals were exposed to acute decompression in a hyperbaric chamber. The appearances that
they described are consistent with the findings seen
in stress failure.
The mechanism of stress failure has clear implications for therapy. The main objective should be to
reduce the pulmonary artery pressure. The pressure
is high because of hypoxic pulmonary vasoconstriction, and the best way to reduce it is by rapid descent
to a lower altitude, which reduces the alveolar P02. In
addition, oxygen should be given if this is available.
Calcium channel blockers such as nifedipine are also
effective because they reduce pulmonary artery pressure (Oelz et al. 1989).
A recent case report by Grissom et al (2000) indi-

cates that alveolar hemorrhage occurs early in HAPE.

They report a case of HAPE in a climber who made a
rapid ascent of Denali, Alaska, and on whom they
carried out BAL. The fluid yielded an abundance of
hemosiderin-laden macrophages. These have been
reported at necropsy and indicate bleeding into the
alveoli. They appear from 48 h after bleeding.
Bronchoscope was performed in this case less than
48 h after symptoms started so the timing of this
result indicates bleeding occurred well before the
onset of symptoms. This finding is consistent with
capillary stress failure early in the course of the condition due to high pulmonary artery pressure.

19*7.6

Venular constriction

Since patients with HAPE have such a powerful

arteriolar constriction in response to hypoxia, perhaps they have some degree of venular constriction
as well. There is some pathological evidence for this
from Wagenvoort and Wagenvoort (1976). This
would not give high wedge pressures because when
the catheter is wedged the blood in that segment runs
off even through constricted venules and the wedge
pressure reflects only the large vein and left atrial
pressures, not the pressure in capillaries when the
blood is flowing. To explain the patchy nature of the
condition one must further postulate that the venular constriction is uneven.

19*7.7

Arterial leakage

Severinghaus (1977), impressed with the extraordinarily high pulmonary artery pressure in these patients,
suggested that perhaps the fluid leak was upstream of
the resistance vessels (i.e. in the arteries). He pointed
out that when there was generalized arterial vasoconstriction, Laplace's law would mean reduction in diameter of small vessels but distension of large vessels (even
though their wall tension was as great or greater).
Radiography frequently shows distended hilar vessels
(Marticorena et al. 1964). These larger vessels, not
designed for such high pressure, suffer minor ruptures
or fenestrations, which then leak high protein fluid and
eventually red cells. The leakage is into the perivascular spaces which, when full, 'back up' to eventually
cause alveolar flooding. This sequence occurs wherever
the initial leak takes place since the perivascular space
is the low pressure region of the lung.

Mechanisms 245

Some evidence for such a mechanism was provided by two studies in animals (Milledge et al. 1968,
Whayne and Severinghaus 1968) and in excised dog
lungs (Iliff 1971). This evidence was reviewed by
Severinghaus (1977) who quoted Hultgren's report
on two horses that died suddenly after running at
altitude. Both were found to have a ruptured pulmonary artery. Both this and the preceding hypothesis would account for exercise being a risk factor
since it increases both flow and pressure in the pulmonary artery.

19*7*8

Multiple pulmonary emboli

Multiple scattered pulmonary emboli, even of inert

substances, such as glass beads, cause a rapid profuse
pulmonary edema in animals (Saldeen 1976) and
this has been shown to be of the protein-rich,
increased permeability type (Ohkuda et al. 1978).
The finding in postmortem studies of frequent vascular thrombi and fibrin clots has led to the
microembolization hypothesis for HAPE on the
premise that there is a derangement of the clotting
system. The effect of hypoxia on coagulation has
been studied by a number of workers (section
18.5.4). It seems that most clotting factors are unaffected by hypoxia; they are not disturbed in AMS.
Some evidence of in vivo fibrin formation was found
by Bartsch et al. (1987) in patients with HAPE but
this was considered to be an epiphenomenon and not
causative. If it does occur it will cause further deterioration in the patient. It is possible that changes in
the red cells with hypoxia might alter their rheological properties and be a factor in AMS and HAPE.
However, Reinhart et al. (1991) found no difference
between subjects with and without AMS with respect
to a number of rheological parameters.
It has even been suggested that rapid ascent may
cause bubble formation by decompression and thus
air microembolization (Gray 1983). If this were the
case, HAPE should be much more common in chamber studies than in the mountains, but this is not so.

19*7*9 Hypoxia. vascular permeability

and inflammation
Hypoxia may increase vascular permeability, either
directly or, more likely, via the release of chemical
mediators. Against this suggestion is evidence that, in

dogs, hypoxia does not alter the threshold for edema

formation at a given microvascular pressure (Homik
et al. 1988). However, it may require some other
agent acting with hypoxia to produce the effect, as
suggested by the work of Larsen et al. (1985). They
showed in rabbits that neither hypoxia alone nor
activation of the complement system (by infusion of
cobra venom) alone caused pulmonary edema, but
the two insults together did. Such a mechanism may
well produce secondary intravascular coagulation,
which would result in further pulmonary edema. On
the other hand Duplain et al. (1999b) found in a
group of HAPE-susceptible individuals, some of
whom developed HAPE at altitude, that there was no
tendency for the exhaled nitric oxide to increase with
HAPE. Exhaled nitric oxide is a marker for inflammation, so this is evidence against inflammation
being a factor in the genesis of HAPE.
Recently Swenson et al. (2000) found, in a group
of HAPE-susceptible subjects taken to 4559 m, that
their BAL fluid did not show an increase in inflammatory markers or neutrophils on the day after
arrival at altitude, whereas increased red cells and
protein (compared with control subjects) were
found. Most of the subjects progressed to overt
HAPE. This finding also suggests that inflammation,
if it plays a part in HAPE, does so late in the course of
the condition and that capillary stress failure is likely
to be the initiating mechanism.

19*7*10

Hypoventilation

Grover (1980) has pointed out that hypoventilation

has two disadvantages for a subject in relation to
HAPE. It will mean that the subject is more hypoxic
at a given altitude than a subject with the normal altitude hyperventilation and also has a higher Pcc,2. The
higher Pcc,2 means that there is no peripheral vasoconstriction and reduction in plasma volume on
going to altitude; hence the plasma osmotic pressure
is not raised. The subject is, therefore, more susceptible to pulmonary edema. A number of studies have
found subjects with a history of HAPE to have low
HVR (Hackett et al 1988b, Matsuzawa et al 1989).
This might lead to relative hypoventilation at altitude, although Hackett et al concluded that the low
HVR played a permissive rather than a causative role
in the pathogenesis of HAPE, allowing hypoxia to
cause depression of ventilation. They found oxygen

246 High altitude pulmonary edema

breathing increased ventilation in some of their subjects at altitude.

concomitant or even previous respiratory infection is

an important risk factor for HAPE.

19.7*11

19.7.13 Defective transepithelial

sodium transport

Neurogenic pulmonary edema

In some cases of head injury, a form of acute pulmonary edema is found which can be mimicked in
experimental animals by creating lesions in the
fourth ventricle. High levels of catecholamines are
found, and the edema can be prevented by pretreatment with a-adrenergic blocking drugs. It is
assumed therefore that the edema is caused by a
surge of sympathetic activity. During the first few
days at altitude there is increased sympathetic activity and possibly a similar mechanism is at work. The
effectiveness of the OC-blocker phentolamine in
HAPE (Hackett et al 1992) suggests that this may be
the case.

19.7.12

Infection

Before 1960 many cases of HAPE were attributed to

pneumonia. Although in many cases infection plays
no part in HAPE, in some it may be a factor,
especially in those individuals who are not normally
susceptible to AMS but on one occasion succumb.
Carpenter et al. (1998) showed that rats given a
mild respiratory infection and allowed to recover had
greater lung edema and higher cell counts and protein concentration in BAL fluid when exposed to
10 per cent oxygen a week later than control rats.
This gives support to the clinical impression that a

Recent studies by Scherrer and colleagues have reinforced the proposition that pulmonary hypertension
by itself does not cause pulmonary edema (section
19.7.3; Sartori et al. 1999). However, in transgenic mice
with disruption of the gene for the oc subunit of the
amiloride-sensitive epithelial sodium channel, hypoxia
did induce pulmonary edema. The same group has
found a similar defect in epithelial ion transport in
HAPE-susceptible human subjects (Lepori etal. 1999).

19.7.14

Mechanisms: conclusions

The various mechanisms discussed are not mutually

exclusive and it is probable that the genesis of HAPE
is multifactorial. The importance of various factors
may be different in individual cases. For example,
infection may play a role in some subjects, though
certainly not in the majority. Some mechanisms may
be important in the initiation of the condition,
others in its progression. At present it is not possible
to be dogmatic about which mechanism is most
important in the initiation and development of
HAPE. However, the mechanism of abnormally
powerful pulmonary hypoxic vasoconstriction,
which is uneven and leads on to capillary stress failure, seems to have the most evidence in its favor.

20
High altitude cerebral edema
20.1
20.2

Introduction
Clinical aspects

247
248

SUMMARY
High altitude cerebral edema (RACE) is a severe
form of acute mountain sickness (AMS) characterized by the same symptoms, headache, malaise,
fatigue, etc., but progressing to ataxia, hallucinations, coma and death. Signs include papilledema,
extensor plantar responses and other neurological
signs. There may be mild fever, cyanosis, increased
pulse and respiratory rates. Computerized tomography and postmortem appearance indicate cerebral
edema and magnetic resonance imaging (MRI) scans
show lesions in the splenium and corpus callosum.
In untreated cases remaining at altitude, death
occurs in a few hours or days.
The incidence of HACE is rather less than for high
altitude pulmonary edema (HAPE). Many patients
have a mixed picture with signs and symptoms of
both conditions.
Prevention of HACE is the same as for AMS, that
is, to make a slow ascent to altitude and to descend if
symptoms do not improve. The diagnosis is made on
the history and clinical examination. In a patient
with symptoms of AMS, if any neurological signs
appear or if there is any clouding of consciousness or
hallucinations then HACE is the likely diagnosis.
Often the earliest sign is ataxia, which is easily missed
in a patient lying in a tent with a headache, especially
as the patient may be irritable and insist that he is all
right.
The most important action in treatment, as in

20.3

Mechanisms

250

HAPE, is to get the patient down. If this is impossible, or while awaiting evacuation, oxygen will help
if available. Dexamethasone 4-8 mg has been shown
to relieve the neurological symptoms and signs and
treatment in a portable compression bag (Gamow or
Certec) is also beneficial, at least for a few hours.
Recovery is often rapid on descent but a number of
cases have been described in which recovery was
delayed by days or weeks.
The mechanism of development of cerebral edema
is not understood. It is probably the same as in benign
AMS to start with but instead of being self-limiting it
progresses to an advanced stage giving rise to the signs
and symptoms described and eventually to death. The
consensus at present is that the edema is vasogenic in
origin with an increase in the permeability of the
blood-brain barrier. Various hypotheses have been
advanced to account for this and are discussed.

20.1

INTRODUCTION

The symptoms of benign AMS are probably due to

mild cerebral edema, which, though unpleasant, is
not serious. In a small minority of cases the condition progresses to more severe symptoms.
Unmistakable signs of cerebral edema and increased
intracranial pressure become manifest and progress
to coma. Death can be expected if the patient is not
treated. This malignant form of AMS is called high
altitude cerebral edema (HACE).

248 High altitude cerebral edema

Ravenhill (1913) called the condition 'puna of a

nervous type'. He describes three cases who
recovered on being sent down to low altitude. As
with acute pulmonary edema of high altitude, his
work was forgotten and it was only during the 1960s
that this serious form of acute cerebral edema of high
altitude was again described (e.g. Fitch, 1964; Singh
etal 1969b).

20.2
20.2.1

CLINICAL ASPECTS
Symptoms and signs

Patients usually have the symptoms of benign AMS

(Chapter 18). They may have headache, loss of
appetite, nausea, vomiting and photophobia. Their
climbing performance falls off, they may be irritable
and wish only to be left alone. It can be difficult to
decide the point at which these benign symptoms
have progressed to malignant AMS, but the appearance of ataxia, irrationality, hallucinations or
clouding of consciousness should alert one to the
likelihood that the patient now has HACE. The
patient may report blurring of vision which may be
due to retinal hemorrhage (section 22.9) or to
papilledema, which may be evident on examination
of the retina. The reflexes may be brisk and later the
plantars may become extensor.
There may be ocular muscle paralysis with
diplopia. The pulse is often rapid and cyanosis usual.
Often there is also an element of pulmonary
edema with signs and symptoms of that condition as
well (sections 19.2.3, 19.2.4). As the condition
progresses all symptoms and signs become more
evident. The headache becomes worse, the ataxia
intensifies so that the patient can no longer sit up
(truncal ataxia). As coma comes on, the breathing
becomes irregular. Death may occur in a few hours
or in a day or two in untreated cases.
20.2.2

Case histories

CASE 1 (HOUSTON AND DICKINSON 1975)

A 39-year-old Japanese woman flew from 1500 m to
2750 m and during the next 2 days climbed to
3500 m, where she developed a severe headache. On
day 4 at 3800 m she began to vomit. On day 5 at

3960 m she became breathless and weak, was vomiting and needed assistance to walk. On day 6 she lost
consciousness and was carried down to 3350 m
where she was found to be deeply unconscious and
cyanosed, with a temperature of 40.6 C and a pulse
of 140 beats/mm"1. Crackles filled the chest. Reflexes
were brisk and plantars flexor. Slight papilledema
was present. She was treated with oxygen, frusemide
and penicillin. On day 8 she was flown to hospital at
1500 m where she was found to be in the same condition but with extensor plantar reflexes. Lumbar
puncture showed a pressure of 270 mm H2O and the
cerebrospinal fluid (CSF) was normal. She slowly
improved over 2 weeks and eventually recovered
completely.
Comment
The symptoms of HACE are dominant in this case
but the patient also had signs of HAPE.
CASE 2 (DICKINSON ET AL 1983)
A 46-year-old man trekked from 1500 m to 3650 m
in 2 days. On the way he began to feel unwell, was
tired, anorexic and later began to vomit. At 3650 m
he became unconscious and was evacuated to hospital at 1500 m. On examination he was deeply unconscious, responding only to pain. He was cyanosed
and hyperventilating. There were crackles and
wheezes in the lungs; papilledema and retinal
hemorrhage were present. Respirations were 40
min"1, the pulse was 120 mhr1, and the temperature
40 C. He remained unconscious and died after
4 days in hospital.
Comment
This is a typical case of HACE, which seemed to have
reached an irreversible stage before descent.
CASE 3 (HOUSTON AND DICKINSON 1975)
A 42-year-old fit man reached 3600 m from sea level
in a few days. He spent 2 days at this altitude and on
day 3 climbed to 4940 m, returning to sleep at
3960 m. On day 4, after carrying about 25 kg to
4940 m, he complained of severe headache, and went
to sleep on arrival at the camp. Next morning he was
confused and unable to talk coherently. He could not
coordinate hand and foot movements and was
disorientated in time and space. He was carried down
to 3600 m where he became coherent and was able to
walk without assistance. He was given an intra-

Clinical presentation 249

muscular steroid and by late afternoon seemed

normal. The next day he was taken down to 2130 m
where he was completely normal.
Comment

A typical case of HACE, where prompt action in

bringing the patient down saved his life.
CASE 4 (ABRIDGED FROM HOWARTH 1999)

A 42-year-old member of a scientific expedition had

trekked to Kangchenjunga Base Camp (5100 m) in
Nepal and spent a week at this altitude including
climbing twice to about 5400 m on day outings. He
had had no sickness during all this time. With three
companions he set out to climb a 6200 m peak on the
return trek. On the first day from Base Camp their
porters took the wrong route to their intended camp
at 5500 m, necessitating some climbing over very
rough ground. During the early part of the day the
patient had been going strongly but in the later part
he was slow and reached camp at 2.45 p.m., cold and
exhausted. He complained of a bad headache but took
some hot soup and painkillers. AMS was diagnosed
and it was hoped he would improve with rest.
However, over the next 2 h he deteriorated and became
ataxic. He was given acetazolamide and dexamethasone but vomited most of the tablets. Evacuation was
started but it required a man on each side to support
him and over the boulder-strewn ground going was
very slow. He continued to deteriorate and they had
to stop for rest every 20 yards or so. The party was
benighted but fortunately was able to radio other
members of the expedition for help. The rescue party
met them with oxygen and injectable dexamethasone
after which the patient improved though descent, over
now steepening scree, was still very slow. A temporary
camp at about 4900 m was reached at 11.30 p.m. By
next morning the patient was much better and during the day was able to walk slowly back to Base Camp.
Comment

This case illustrates the unpredictability of AMS in

that typical HACE developed in a climber who would
seem to have acclimatized well. In some subjects who
have no problems up to a certain point there seems
to be a critical altitude above which they quite
abruptly start having symptoms. It also emphasizes
the importance of making an early diagnosis and
getting the patient down as soon as possible - easier
with hindsight of course.

20.23

Investigations

Blood counts and blood biochemistry are usually

normal. Chest radiograph may show evidence of
concomitant pulmonary edema, whilst lumbar
puncture (which is not normally indicated) usually
shows raised pressure but normal CSF. Computerized tomographic scanning of the brain in 12
patients with HAPE and HACE (Koyama et al.
1984) showed evidence of cerebral edema with
diffuse low density of the entire cerebrum and
compression of the ventricles. Recovery to normal
computerized tomography findings occurred within
a week in three cases but persisted for 1-2 weeks in
two cases; one case took over a month to clear. MRI
findings are detailed in section 20.3.1.

20*2.4

Treatment

The treatment for HACE is very similar to that for

HAPE; that is, get the patient down to lower altitude
as soon as possible. Oxygen therapy is obviously
advised while awaiting evacuation, but often is only
of marginal benefit. Dexamethasone has been
shown to be of benefit in a double-blind, randomized, placebo-controlled trial in AMS (Ferrazzini et
al. 1987). It is particularly the cerebral symptoms
which seem to be helped by this drug, so it should
certainly be used in this situation. The dose used in
the trial was 8 mg initially, followed by 4 mg
6 hourly. Probably dexamethasone is to be preferred
to diuretics, although they can be tried if response
to the former is not adequate,. Enthusiasm for
dexamethasone should be tempered by the finding
that, although symptoms are relieved, the physiological abnormalities (fluid shifts, oxygenation, sleep
apnea, urinary catecholamine levels, chest radiograph, perfusion scans and the results of psychomotor tests) were not improved (Levine et al. 1989).
The drug is no substitute for descent. Portable
hyperbaric bags (Gamow bags) are now available
and their use in HAPE is discussed in Chapter 19. In
HACE their use is less well documented but, if
available, they can certainly be tried. Their use may
make it possible for a patient to then descend
unaided instead of having to be carried. Recovery
after descent may not be as rapid as is usually the
case with HAPE (Dickinson 1979; and see Cases 1
and 2).

250 High altitude cerebral edema

20.2*5

Postmortem appearance

There have been a few reports of postmortems in

HACE (Singh et al. 1969b, Houston and Dickinson
1975, Dickinson et al. 1983). The usual findings in
the brain are of cerebral edema with swollen,
flattened gyri, and compression of the sulci. There
may be herniation of the cerebella tonsils and unci.
Spongiosis, especially in the white matter, may be
marked. In many cases there are widespread
petechial hemorrhages; in some there are antemortem thrombi in the venous sinuses or there may
be subarachnoid hemorrhages, but there seems to be
considerable variation in the findings. It must always
be remembered that the few cases that reach autopsy
are highly selected and may well be unrepresentative
of the condition as seen clinically in the field.

20.2.6

Incidence and etiology

The incidence - like that of HAPE - is difficult to

determine and depends upon the rate of ascent and
therefore on terrain, logistics and the pattern of
movements of people from sea level to altitude. It
also depends upon definition, where the distinction
between severe cases of benign AMS and mild HACE
is impossible. Many cases show a mixed picture of
HAPE and HACE. However, Hackett et al (1976)
had five cases out of 278 ti;ekkers arriving at Pheriche
(4243 m) in Nepal giving an incidence of 1.8 per
cent, rather less than that for HAPE.
The age and sex distributions, like those for AMS,
show no group to be immune. Possibly the younger
male is rather more at risk, perhaps because he is
more likely to push on to higher altitude with
symptoms, a feature of many histories in fatal cases.
People native to high altitude can become victims of
HACE. The impression is that the incidence in them
is lower but there are no good published data.

203

MECHANISMS

The mechanism for the development of cerebral

edema at altitude is reviewed in Chapter 18. Hypoxia
seems to induce an increase in extracellular fluid
(ECF). It may also cause increased microvascular
permeability. Hypoxia certainly increases cerebral
blood flow (Severinghaus et al. 1966b), particularly

when there is no marked reduction in -PCo2- However,

a study by Jensen et al. (1990) found no correlation
between increase in cerebral blood flow and AMS.
These same factors may become more pronounced
to cause the symptoms of HACE, but there may be
others. The question of why certain individuals are
susceptible whereas others are not is as puzzling in
HACE as in other forms of AMS, although one possible factor might be the relative sizes of the brain and
cranial cavity. In a recent review of etiology, Hackett
(1999) discusses this 'tight fit' hypothesis: those with
a tight fit brain in the box of their cranial cavity will
have a greater rise in pressure for a given increase in
fluid volume in the brain. Those with looser brains
are less susceptible. As we get older our brains shrink
and this may be a why older people are less susceptible to AMS and HACE.

203.1 Cytogenic or vasogenic cerebral

edema
There is no doubt that the symptoms of HACE (and
probably those of AMS) are due to cerebral edema
and increased intracranial pressure. A recent point of
debate has been whether the edema is cytogenic,
edema of the brain cells, or vasogenic, movement of
fluid and protein out of the vascular compartment.
Hackett et al. (1998) reported MRI scans in nine
patients with HACE compared with three with
HAPE and three who had been to altitude with no
illness. They found intense T2 signals in white matter,
especially in the splenium and corpus callosum.
There were no lesions in the gray matter. These findings suggest that the edema was vasogenic and that
the problem may lie with the blood-brain barrier.

203.2

Venous thrombosis

Venous thrombosis has been found on computerized

tomographic scan in one patient (Asaji et al. 1984)
and in some postmortem studies of HACE. It may
develop late in the condition as a consequence of
intracranial hypertension. It will certainly exacerbate
the condition.

20.33

Cellular edema

In profound hypoxia, the ATP-dependent sodium

pump eventually begins to fail; sodium concentra-

Mechanisms 251

tion rises in the cell and water follows to maintain

osmotic equilibrium (Fishman 1975). This may be
the cause of further cerebral edema in established
cases, especially in those with pulmonary edema
causing further hypoxia. However, it cannot be the
cause of problems at the start of RACE because the
hypoxia is not sufficiently profound.

203.4
factor

very effective in preventing angiogenesis and it may

be this action which explains its effectiveness in
RACE. This theory received support from the finding of VEGF mRNA in rat brains after only 3 h of
hypoxia. The level reached a peak of three times control at 12-24 h (Xu and Severinghaus 1998). This
could explain the increased permeability of the
blood-brain barrier and the vasogenic edema.

Vascular endothelial growth

Severinghaus (1995) suggested that the same factors,

operating in situations of angiogenesis, may be
involved in RACE. Hypoxia stimulates the release of
transforming growth factor (TGF) which attracts
macrophages. These in turn release vascular
endothelial growth factor (VEGF) and other factors
which eventually give rise to growth of new
capillaries. The more immediate effect is to increase
capillary permeability as capillary basement
membranes are broken down. Severinghaus suggests
that, even earlier than these events, hypoxia may
cause osmotic brain swelling. Dexamethasone is

203.5

Nitric oxide and cerebral edema

Clark et al. (1999) suggested that the mechanism of

cerebral edema in RACE may be via the induction
of inducible nitric oxide synthase (iNOS) in the
brain by hypoxia. This gives rise to increased levels
of nitric oxide which causes edema by increasing
vascular permeability. In most cases this is quite
mild and self-limiting, giving rise to the symptoms
of benign AMS. However, if there are even low
levels of cytokines as well, due to a mild infection
for instance, there will be a synergistic effect on
iNOS induction and permeability. This results in
HACE.

21
Subacute and chronic mountain sickness
21.1

Subacute mountain sickness

252

SUMMARY
Subacute mountain sickness is a condition affecting
either infants born or brought up to altitude within
their first year, or adults remaining at extreme
altitude for weeks or months. In Tibet, the infants
are usually the children of lowlanders, Han
Chinese; the highland Tibetan infants are relatively
immune. As the condition develops the infants
become breathless, irritable and edematous. The
pathology is of pulmonary hypertension and right
heart failure. In adults, it has been reported in
Indian soldiers stationed at about 6000 m for long
periods. Again the signs of right heart failure are
prominent. Descent results in reversal of signs and
symptoms.
Chronic mountain sickness (CMS) was first
recognized by Carlos Monge M. in Peru and is also
known as Monge's disease. It is found in all
populations who remain at altitude for a number of
years. The incidence is increased with altitude and
with age; it is higher in males than in with females. In
Tibet at least, it is more common in immigrant Han
Chinese than in native Tibetans.
In cases without overt lung disease various factors
which cause relative hypoventilation, such as a
reduced hypoxic ventilatory drive or disturbed
breathing patterns during sleep, may be involved in
the mechanism. The commonest underlying condition is chronic obstructive lung disease (chronic

21.2

Chronic mountain sickness

253

bronchitis, emphysema) often associated with

smoking; tuberculosis, kyphoscoliosis and other lung
diseases are also found as contributory causes. These
conditions make the patient more hypoxic and
increase the stimulus to erythrocytosis.
The symptoms that result from this excessive
erythrocytosis are rather vague and include headache, dizziness, physical and mental fatigue, anorexia
and breathlessness. Signs are few and include
cyanosis and a florid complexion.
Prevention, apart from remaining at low altitude,
can only be directed at secondary risk factors such as
smoking and occupational dust air pollution.
Relocation to low altitude cures the condition but
many patients are not able to take this option. The
removal of a unit of blood is beneficial but needs to
be repeated as the hemoglobin concentration rises
again. Respiratory stimulants have been used with
reported success.

21.1
21.1.1

SUBACUTE MOUNTAIN SICKNESS

Introduction

Two forms of subacute mountain sickness have been

described, one in infants born at low altitude and
taken to high altitude (Sui et al 1988) and the other
in adults who have spent some months or more at
extreme altitude (Anand et al. 1990).

Chronic mountain sickness 253

21.1.2 Infantile subacute mountain

sickness
The Spaniards who first colonized the Andes became
well aware that their infants did not thrive if born at
high altitude. They made it their practice to arrange
delivery at low altitude and not to bring their babies
to high altitude before 1 year of age. The lowland Han
Chinese colonists of Tibet face the same environmental problem. Wu and Liu (1995) described a
Chinese infant of 11 months born in Lhasa (3658 m)
who presented with dyspnea, cyanosis and congestive
heart failure. At postmortem, marked right ventricular hypertrophy and muscular thickening of the
peripheral pulmonary artery tree was found. There
was no other pathology such as congenital heart
disease and the authors called the condition high
altitude heart disease. Sui et al. (1988) reported the
postmortem findings on 15 infants who died in Lhasa
of a syndrome they called infantile subacute mountain sickness. The presenting symptoms were commonly dyspnea and cough, with often sleeplessness,
irritability and signs of cyanosis, edema of the face,
oliguria, tachycardia, liver enlargement, rales in the
lungs and fever. The majority of infants had been
born at low altitude but two were born at high
altitude, one of Han and one of Tibetan parents. The
condition was usually fatal in a matter of weeks or
months. The postmortem findings were of extreme
medial hypertrophy of muscular pulmonary arteries
and muscularization of pulmonary arterioles. There
was massive hypertrophy and dilatation of the right
ventricle and of the pulmonary trunk.
21.13
Adult subacute mountain
sickness
Anand et al. (1990) described the adult form in 21
soldiers who, after a full acclimatization period, had
been posted to between 5800 m and 6700 m for
several months (mean 1.8 years). They presented
with dyspnea, cough and effort angina. The signs
were of dependent edema. They were treated at high
altitude with diuretics with improvement. When
they were evacuated to low altitude by aircraft they
were found to have cardiomegaly with right
ventricular enlargement and, in most cases, pericardial effusion. The pulmonary artery pressure was
elevated (26 mm Hg) and rose significantly on mild

exercise to 40 mmHg. Recovery was rapid after

descent from high altitude. The mechanism includes
a generalized increase in the volume of the fluid
compartments of the body and total body sodium,
even in subjects without overt disease at these
altitudes for this length of time (Anand et al. 1993).
The increase in central blood volume is the probable
cause of the decrease in forced vital capacity, and the
radiographically engorged pulmonary vessels found
in the subjects of Operation Everest II (Welsh et al.
1993). It would seem that this subacute mountain
sickness is the human form of a similar condition
affecting cattle taken to high altitude, and known as
brisket disease (Hecht et al. 1959). The brisket is the
loose skin area of the cow's neck, which is dependent
and becomes swollen with edema fluid in this
condition.

21.2
21.2.1

CHRONIC MOUNTAIN SICKNESS

Historical

In 1925 Carlos Monge M. reported a case of polycythemia in a patient from Cerro de Pasco (4300 m)
in Peru to the Peruvian Academy of Medicine
(Monge 1925). In 1928 he reported a series of such
patients with red cell counts significantly higher
than normally found at altitude (Monge C. and
Whittembury 1976). (Note: Carlos Monge M. is the
father and Carlos Monge C. the son: the M and C
are the initial letters of the mothers' names, as is
Spanish custom.) This condition of CMS has come
to be known also as Monge's disease. The 1935
international expedition, led by Bruce Dill, reported
one case of CMS in the English literature (Talbott
and Dill 1936). In 1942 Hurtado published detailed
observations of eight cases, outlining the symptomatology and hematological changes at altitude and
the effect of descent to sea level and return to altitude (Hurtado 1942).
Outside South America, CMS was observed in
Leadville (3100 m), a mining town in Colorado,
USA, by Monge M. in the late 1940s (Winslow and
Monge 1987, p. 15) and from the 1960s the condition
has been studied there by Weil and colleagues (1971)
from Denver (section 21.3.3). Reports of CMS from
the Himalayas indicate the condition to be prevalent
in immigrant Han Chinese in Lhasa (3658 m) but

254 Subacute and chronic mountain sickness

rare in the indigenous Tibetan population (Pei et al.

1989).
21*2.2

Clinical aspects of CMS

SYMPTOMS

Patients typically have rather vague neuropsychological complaints including headache, dizziness,
somnolence, fatigue, difficulty in concentration and
loss of mental acuity. There may also be irritability,
depression and even hallucinations. Dyspnea on
exertion is not commonly complained of, but poor
exercise tolerance is common and patients may gain
weight. The characteristic feature of the disease is
that the symptoms disappear on going down to sea
level, only to reappear on return to altitude.

(Penaloza and Sime 1971, Kryger et al. 1978a). The

lower Pa02 is partly due to hypoventilation as shown
by the increased Pac02 and partly (in many cases) by
an increased alveolar-arterial oxygen tension
((A-a)O2) gradient. Manier et al. (1988) found a
mean of 10.5 mmHg in CMS patients at La Paz
(3600 m) compared with the normal (A-a)O2 of
2.9 mm Hg at this altitude. Using the multiple inert
gas technique, they attributed most of this to
increased blood flow to poorly ventilated areas of
lung rather than to true shunting. Tewari et al.
(1991) found a reduced diffusing capacity in lowland
soldiers with excessive polycythemia, which
improved after descent and return to a normal
hematocrit. In some cases standard pulmonary
function tests show abnormalities indicating
obstructive and/or restrictive defects, suggesting that
patients have coexisting chronic lung disease.

SIGNS

Although normal people are mildly cyanotic at an

altitude of 4000 m, patients with CMS stand out
since, with a high hemoglobin concentration and
lower oxygen saturation, they have a far higher
concentration of reduced hemoglobin. In Andean
Indians, the population with the greatest number of
patients, the signs may be florid:
The combination of virtually black lips and wine
red mucosal surfaces against the olive green
pigmentation of the Indian skin gives the patient
with Monge's disease a striking appearance (Heath
and Williams 1995, pp. 193).

The conjunctivae are congested and the fingers may

be clubbed. In Caucasians and at lower altitudes such
as Leadville (3100 m), the appearances are rather less
striking, resembling patients with polycythemia
secondary to hypoxic lung disease at sea level. Some
patients show very little in the way of signs.

HEMODYNAMICS AND PATHOLOGY

The very high hematocrit increases the viscosity of

the blood enormously. The systemic blood pressure
may be moderately elevated and the pulmonary
artery pressure is significantly higher than healthy
high altitude residents. Penaloza etal. (1971) found a
mean pulmonary artery pressure of 64/33 mm Hg in
10 cases of CMS compared with 34/23 mmHg in
controls. Cardiac output was not significantly
different, so that calculated resistance was just over
twice that of controls.
As might be expected these hemodynamic changes
lead to increased right ventricular hypertrophy and
associated electrocardiogram (ECG) changes. A
recent study found that 90 per cent of cases of CMS
had ECG evidence of right ventricular hypertrophy
(Halperin et al. 1998). There is also thickening of the
pulmonary arteries to a greater degree than in normal
residents at high altitude (Arias-Stella et al. 1973).

INVESTIGATIONS

The red cell count, hemoglobin concentration and

packed cell volume are raised; values as high as
28.0 g dlr1 hemoglobin and a packed cell volume of
up to 83 per cent have been recorded (Hurtado
1942). Like secondary polycythemia at sea level and
unlike polycythemia rubra vera there is no increase
in white cell numbers. Blood gases, compared with
healthy controls at the same altitude, show a higher
Pac02 and lower Pa02 and oxygen saturation

PREVENTION

Descent to low altitude without return is a sure

preventative but not an option for many altitude
residents whose livelihood depends upon their work
at altitude. Attention to any secondary risk factors
such as smoking is obvious. Since many patients are
miners, efforts can also be made to avoid occupational health risks such as dust and air pollution,
but these are frequently difficult to eliminate.

Chronic mountain sickness 255

TREATMENT

As already mentioned, symptoms and signs classically

clear up on going down to sea level. However, many
patients want to remain at altitude for family or
economic reasons. In these cases, venesection is
beneficial. Venesection not only lowers the raised
hematocrit but also improves many of the neuropsychological symptoms. It also improves pulmonary
gas exchange (Cruz etal. 1979) and exercise performance in some subjects (Winslow and Monge 1987,
p. 212). In Leadville, Colorado, with about 60 patients
being regularly bled for therapeutic purposes, the
blood bank has no need of any other donors (Kryger
etal. 1978a)!
An alternative to venesection for residents at high
altitude is the long-term use of respiratory stimulants. Kryger et al. (1978b) have reported success
with medroxyprogesterone acetate. They showed a
fall in hemoglobin concentration after 10 weeks'
treatment in 17 patients. The drug increased ventilation and P02 and reduced PC02 by a modest
amount. Although the changes in blood gases were
small, they suggest that the main benefit may have
been in oxygenation at night since hypoxemia may
be much greater then. The only side effect reported
was of loss of libido in four patients. In all but one,
this could be overcome by lowering the dose to a
level that still kept the hemoglobin concentration
down. In one patient the dose had to be reduced to
a point which did not hold down the hemoglobin
concentration.
There do not seem to have been any reported trials
of other stimulants such as acetazolamide, which has
been shown to be effective in preventing AMS
(Chapter 18).

21.2.3

Epidemiology of CMS

ANDES

CMS is found most commonly in the Andes, where it

was first described mainly affecting the local
Amerindians, especially the Quechuan population
living on the altiplano at altitudes about
3300-4500 m. Men are affected far more commonly
than women. The average age is 40 years with a range
from 22 to 51 years in one reported series (Penaloza
et al. 1971). Occasional cases are seen in expatriate
mining company staff. It used to be thought that

CMS was virtually confined to the Andes but this is

not the case, as is discussed below.
HIMALAYAS AN DTI BET

Until recently there have been few reported cases of

CMS in the Himalayas. Winslow noted one Sherpa
on the American Medical Research Expedition to
Everest to have a hematocrit of 72 per cent (Winslow
and Monge 1987, p. 17). Pei et al (1989) describe
their experience of CMS in Lhasa (3658 m). The
condition is not uncommon among male cigarettesmoking Han Chinese. These subjects had
immigrated some years before becoming polycythemic and then displayed the usual signs and
symptoms of CMS. In a 12-month period there were
24 patients admitted to their hospital with CMS. All
were male, 23 were Han and only 1 Tibetan. Six were
nonsmokers, the rest, including the one Tibetan,
were smokers. The mean duration of altitude exposure in the lowlanders was 26 years (range
9-43 years). However, though the incidence in
Tibetans may be less than in Han immigrants, CMS
is now being reported in this population. Wu et al.
(1992) reported a series of 26 cases in native-born
Tibetans living at between 3680 m and 4179 m with
typical symptoms of CMS and hemoglobin concentration of 22.2 g dlr1 mean compared with
16.6 g dL-1 in healthy controls at the same altitude.
In Himalayan residents, hemoglobin concentration tends to be lower than the values from the
Peruvian Andes, although much of this difference
disappears if results from mining towns are excluded
(Frisancho 1988). It is speculated that this may be
because the geography allows residents to move to
lower altitudes more easily than from the altiplano of
the Andes, and the way of life of the Sherpas, with
seasonal migration, contributes to this movement in
altitude. Like the inhabitants of the Andes, Tibetans
live on a high altitude plain and cannot easily move
up and down.
Although more evidence is needed it would seem
that people of Tibetan stock are less at risk of CMS
than Andean highlanders, and certainly than lowland
Han subjects long resident at altitude. This may be
due to genuine genetic adaptation to altitude over
very many generations.
A recent review comparing incidence of CMS in
the Andes with that in Tibet seems to bear out this
earlier speculation (Moore et al. 1998b). This review

256 Subacute and chronic mountain sickness

also presents more evidence on incidence at various

altitudes, men versus women, and Tibetan versus
Han Chinese.
NORTH AMERICA

The condition is well recognized in Leadville,

Colorado (3100 m). Kryger et al (1978a) described
20 cases, all male, and mentioned that, of about 60
cases known to physicians there, only 2 were female.
One case of apparently classical CMS in a 67-yearold woman has been reported from as low as 2000 m
in California (Gronbeck 1984).
21.2*4

Terminology

POLYCYTHEMIA OF ALTITUDE

Opinions differ about the hemoglobin value required

for diagnosis of CMS. A value of 23 g dL"1 has been
used, but it would seem wiser to take into account the
normal value and range for that particular altitude
(Chapter 8), and even then, any given value is rather
arbitrary. Indeed, it has been argued that CMS does
not represent a distinct entity at all and that the hemoglobin values represent merely the 'tail' of a normal
distribution curve (Monge C. and Whittembury
1976). For practical purposes, a value of two standard
deviations above the mean for that altitude can be
considered the cut-off for 'normal'. The 'tail' population may then be considered abnormal and polycythemic for that altitude. Since at this value
symptoms occur, treatment is indicated and therefore
this definition has practical implications.
This concept is in line with the conclusions of a
monograph on CMS by Winslow and Monge, C.
(1987, p. 204), who define it in terms of a hematocrit
'above the statistical maximum for the altitude in question'. However, they also draw attention to the work
of Cosio who found important differences in hemoglobin concentration between two populations living
in two towns at the same altitude (4600 m) (Winslow
and Monge, C. 1987, p. 37). This illustrates the difficulty of assigning a 'normal' value for a given altitude.

their polycythemia simply secondary to lung disease

which has greater effect because of the altitude?
Arias-Stella (1971) initiated discussion at the Ciba
Symposium on high altitude physiology with a
paper describing a postmortem on a woman with
CMS and kyphoscoliosis. He suggested the use of
the term 'Monge's syndrome' for cases like this,
where there was lung or chest wall disease as a
primary cause, and 'Monge's disease' proper for
cases with no lung disease. The challenge was
thrown out for some pathologist to report a case of
polycythemia in which lung disease had been
excluded by rigorous modern pathological methods.
This challenge has yet to be taken up. The usage of
'Monge's syndrome' has not been generally adopted
and most workers simply refer to patients as having
CMS, Monge's disease or polycythemia of high
altitude, with or without overt lung disease.
CONSENSUS GROUP ON CMS

In 1998 at the World Congress on Mountain

Medicine at Masumoto a group was established to
try to define the terminology of CMS. They had great
difficulty in reaching a consensus on the definitions
to be used. Among other problems discussed were
how to define the level of hemoglobin concentration,
what to do about obvious lung disease and if signs of
pulmonary hypertension should be included in the
definition. However, the following was agreed as a
working definition:
CMS is a syndrome, which occurs in persons long
resident at high altitude and which is characterized
by excessive erythrocytosis and hypoxemia and by
reversibility on descent. It may be classified as
primary (without identified cause) or secondary
(due to underlying condition) (Leon-Velarde 1998).

At the same meeting a scoring system was

proposed by Leon-Velarde but it has yet to be
adopted widely.

21.2*5

Mechanisms of CMS

LUNG DISEASE AND POLYCYTHEMIA

CMS WITH LUNG DISEASE

It is well known that hypoxic lung disease causes

polycythemia in patients even at sea level. Many
patients in the mining towns of the Andean
altiplano smoke and work in dusty occupations. Is

In cases of CMS with definite lung disease, it is easy

to understand that the combination of altitude with
fairly mild lung disease precipitates polycythemia
and cor pulmonale (Fig. 21.1). Removal of altitude

Chronic mountain sickness 257

population are destined to get CMS if they remain

for years at altitude. The HVR decreases with age
(Kronenberg and Drage 1973) and with duration of
stay at altitude (Wiel et al. 1971); perhaps patients
with CMS are those in whom the process is faster
than average (Fig. 21.1).
Kryger et al. (1978a), however, found no difference in HVR between patients and age-matched
controls in Leadville, Colorado. They did find that
their patients had a greater dead-space/tidal volume
ratio and that their ventilation increased on breathing 100 per cent oxygen; they therefore appeared to
have hypoxic ventilatory depression. They concluded
that blunted chemical drive to breathing is not the
cause of CMS.
SLEEP

Figure 21.1 Possible mechanisms in the development of chronic

mountain sickness (CMS). HVR, hypoxic ventilatory response; CBF,
cerebral blood flow; PCV, packed cell volume.

hypoxia by descent to sea level is sufficient to reverse

the process. At altitude, these patients are more
hypoxic than normal people because of their lung
disease, hence their stimulus to erythrocytosis via
erythropoietin secretion is greater and they become
abnormally polycythemic. The importance of lower
respiratory tract disease is emphasized in a study by
Leon-Velarde et al. (1994) which shows that subjects
with chronic lower respiratory disease had higher
hemoglobin concentration, lower 5a02 and higher
CMS symptom scores than healthy controls or subjects with chronic upper respiratory disease.

During sleep, even in normal subjects, the ventilation

is depressed. If there are frequent periods of apnea,
either central or obstructive, Sa02 will be further
reduced and could contribute to the etiology. A
recent study by Sun et al. (1996) found that CMS
patients had more disordered breathing and lower
mean Sa02 values when asleep than a group free of
CMS.
GENDER

Women (at least before the menopause) seem to be

protected from CMS as from the hypoventilation
syndrome (the Pickwickian syndrome) at sea level,
possibly by the stimulating effect of female sex
hormones on ventilation. Leon-Velarde et al. (1997)
compared premenopausal and postmenopausal
women at Cerro de Pasco (4300 m) in Peru and
found significantly higher hematocrit and Sa02, and
lower peak expiratory flows in the postmenopausal
group, supporting the protective role of female sex
hormones.

CMS WITH NORMAL LUNGS

The mechanism in cases with apparently normal

lungs is less clear.
HYPOXIC VENTILATORY RESPONSE (HVR)

Severinghaus et al. (1966a) found that such patients

have an extremely blunted HVR compared with
healthy resident controls of the same age. Maybe
people at the low end of the spectrum for HVR in the

AGE

Age has effects on lung function as well as its effect on

HVR. The Pa02 declines with age and, although this
has little effect on oxygen saturation at sea level, it has
much more effect at altitude because subjects are
already on the steep part of the oxygen dissociation
curve. A study by Leon-Velarde etal. (1993) at 4300m
in Peru found an increasing incidence of CMS with
age. Taking a hemoglobin concentration of above

258 Subacute and chronic mountain sickness

21.3 g dlr1 (the mean plus 2 SD of the total population aged 20-29 years) as 'excessive erythrocytosis',
the incidence at 20-29 years was 6.8 per cent which
increased to 33.7 per cent at age 60-69 years. This
study also found a decreasing vital capacity with age
at altitude, in both those with and without CMS, but
the reduction was significantly more marked in the
CMS group. Sea level subjects showed no reduction
in vital capacity between 20-29 years and 60-69 years.
SUMMARY
Polycythemia results in reduced cerebral blood flow
(Thomas et al. 1977) due to increased viscosity.
There do not seem to have been studies of cerebral
blood flow in CMS but there is no reason to doubt
the assumption that it is reduced. Figure 21.1 shows
the interaction of factors involved in CMS. Altitude
hypoxia and hypoventilation will result in a low Pa02.

This hypoventilatory response may be due to a low

HVR, to hypoxic depression of ventilation or some
unknown cause. If lung function is also reduced by
lung or chest wall disease, this will reduce Pa0z still
further. Aging results in both reduced lung function
and reduced HVR, especially in a life spent at high
altitude, thus further lowering the Pa02. The low Pa02
results in a low 5a02. It also stimulates secretion of
erythropoietin and hence an increase in packed cell
volume. However, it should be noted that a study of
erythropoietin levels in subjects at Cerro de Pasco
(4300 m), although showing the expected higher
mean values at altitude than at sea level, did not
demonstrate any difference between subjects with
and without CMS (Leon-Velarde et al. 1991). The
rise in packed cell volume causes a rise in blood
viscosity and a fall in cerebral blood flow, which, with
a low 5a02, results in chronic severe cerebral hypoxia
and symptoms of CMS.

22
Other altitude related conditions:
neurovascular disorders, eye conditions,
altitude cough, anesthesia at altitude
22.1
22.2
22.3
22.4
22.5
22.6

Introduction
Neurovascular disorders
Platelets and clotting
Splinter hemorrhages
Risk factors for thrombosis
Mechanisms of vascular accidents

260
260
261
263
263
263

SUMMARY

A cluster of neurovascular signs and symptoms has

been reported in mountaineers for many years.
These vary from transient ischemic attacks (TIA),
often with symptoms of dysphasia or transient visual
disturbance or even blindness, to longer lasting
strokes with hemiplegia, etc. The problems usually
occur after some time at altitude and so are not considered part of acute mountain sickness (AMS). The
condition usually resolves rapidly and recurrence is
unusual. However, few patients expose themselves to
altitude risk again. Also reviewed in this chapter is
the effect of altitude on factors involved in clotting,
which in general seem little disturbed at altitude.
Risk factors for thrombosis and mechanisms are
discussed.
Eye problems at altitude include retinal hemorrhage, transient visual disturbance or blindness,
which may be neurovascular or migrainous in origin,
and problems following corneal surgery. Retinal

22 .7
22 .8

Case histories
Management
22..9 Retinal hemorrhage
22 .10 Altitude and corneal surgery
22,.11 High altitude cough
22,.12 Anesthesia

263
265
265
266
267
268

hemorrhage is normally a symptomless, benign condition diagnosed only if the retina is inspected. Small
hemorrhages are seen which clear in a few days. The
incidence is variable, often being over 50 per cent
when looked for. It is usually seen early in altitude
exposure. Only in rare cases, when the hemorrhage
affects the macula, is vision disturbed. Problems after
corneal surgery are confined to patients who have
had radial keratotomy for myopia. In these patients
the hypoxia of altitude results in a change in the
refractive properties of the operated eye, making for
long-sightedness. At extreme altitude this can render
the patient almost blind. The problem resolves after
descent.
Altitude cough, though known for many years, has
only recently been scientifically investigated. It
afflicts most climbers who remain at altitude for
more than a few days and in severe cases can cause
sleep disturbance, fatigue and even fracture of ribs.
Although hyperventilation of the cold dry air at altitude may be a factor, it seems that hypoxia itself is
important. The cough threshold for citric acid is

260 Other altitude related conditions

lowered by stay at altitude and this can be prevented

by therapy with antiasthma inhalers. Altitude also
affects mucociliary function in the nose and this can
be prevented by regular moistening of the nasal
mucosa with saline.
General anesthesia at altitude is dangerous
because of the respiratory depressant effects of anesthetics. They abolish the hypoxic ventilatory
response (HVR) so that ventilation is reduced and
with the low inspired P0l the risk of severe hypoxia is
considerable. This risk of hypoxia extends into the
postoperative period because even small concentrations of anesthetic gases depress the HVR. It is therefore advised that general anesthetic be avoided at
altitude. Either local anesthetic should be used or the
patient brought down to low altitude. If general
anesthetic must be given at altitude, oxygen should
be added at high concentrations.

22.1

INTRODUCTION

Apart from AMS in its various forms and cold

injury, altitude can result in a variety of disorders.
Transient ischemic attacks, attacks of dysphasia or
strokes are encountered indicating an effect of
altitude on the blood supply of the central nervous
system (CNS). The eyes can be affected by retinal
hemorrhage and various disturbances of vision,
altitude cough may be a problem for climbers especially at extreme altitude, and it may be necessary to
give anesthesia at altitude. These conditions are discussed in this chapter.

22.2
22.2.1

NEUROVASCULAR DISORDERS
Historical background

Increasingly, cases with neurological signs, some

transient and others permanent, are being reported
from expeditions at altitude in both lowlanders and
highlanders. These are not associated with AMS, or
high altitude cerebral or pulmonary edema (HACE,
RAPE). It is likely that some have a vascular origin,
such as spasm, thrombosis, embolus or hemorrhage.
Others may be focal neurological disorders or are of
unknown etiology.
Sporadic cases of vascular disorders have been

described in the mountain and geographical literature over the last century (Table 22.1).
In 1895, while exploring the Amne Machin range
in eastern Tibet, Roborovsky, a Russian traveler, suffered a 'stroke' in crossing the Mangur Pass (4270 m).
He described 'a stroke of paralysis which attacked the
right part of my body from head to the toes of my right
foot; my tongue hardly obeyed my will. I lay in a disgusting and unbearable state for eight days.' Over the
next few weeks he gradually recovered and continued
his journey (Roborovsky 1896).
Cases of hemiplegia also occurred on Everest
expeditions in 1924 and 1936. One, a Gurkha soldier,
died, and the other, a Sherpa porter, recovered
(Norton 1925, p. 68, Tilman 1948). Evans (1956,
p. 169) on Kangchenjunga recorded a further fatal
case of hemiplegia in a Sherpa. Each of these three
cases was in a fit young man who had spent a considerable period above 6000 m.
In 1954, a young American mountaineer, stormbound in a tent at 7465 m on K2, developed
thrombophlebitis in the calf and, after a further
2 days, had a hemoptysis. A provisional diagnosis of
pulmonary embolus was made and he was evacuated;
however, during the descent he was swept away in an
avalanche (Houston and Bates 1979).
Shipton (1943), after climbing to 8865 m on
Everest, described an episode of transient aphasia
with severe headache. This was possibly due to a
migraine attack. Apart from severe headache he had
no other symptoms and was fully recovered by the
next morning
Coronary and cerebral thrombosis and cases of
phlebitis of the limbs have been reported (Fujimaki
et al. 1986), as have TIA and transient blindness
(Hackett et al. 1987c, Wohns 1987). Cases of lateral
rectus palsy and diplopia have been described at altitude (Murdoch 1994). At sea level the development
of lateral rectus muscle palsy is usually due to lesions
in the sixth cranial nerve or its nucleus. It is found in
cases of diabetes mellitus, neoplasm and raised
intracranial pressure. At altitude, although raised
intracranial pressure may be present in AMS and
especially HACE, rectus palsy may occur in their
absence.
Migraine with ophthalmoplegia has been reported
at altitude. Its pathogenesis remains uncertain,
although vascular mechanisms are considered
important. Psychological factors may also be important (Jenzer and Bartsch 1993). Unsuspected cases of

Platelets and clotting 261

Table 22.1 Cerebrovascular accidents at altitude. All subjects were male adults. The two patients who died were Sherpas;
the remainder were climbers from low altitude

1895
1924
1938
1943
1954
1961
1978
1982
1983
1986

4300
6000
6400
6400
6000+
6400
6400
8200
6100
4900

7
7
7

6 weeks
7
7-8 weeks
7
1 weeks
7

Several days

1990
1990

4800
5300

9 days
Several days

1994
1994
1995
1997

3867
4242
3660
7600

4 days
12 days
100 mile race
Several days

Right hemiparesis
H em i paresis
Right hemiparesis
Dysphasia
Hemiparesis
Right hemiparesis
Hemiparesis
Left hemiparesis
Semi-conscious
Headache, visual disturbance
Numb right hand,
?migraine
Right hemiparesis
Headache, weak right
hand and right leg,
?migraine
Right lat. rectus palsy
Right lat. rectus palsy
Diplopia
Right hemiparesis,
CT scan edema,
left parietal lobe

Recovered
Died
Recovered
Recovered
Died
Recovered
7

Recovered
Recovered
Recovered
Recovered
Recovered

Recovered
Recovered
Recovered
Recovered

Roborovsky(1896)
Norton (1925)
Til man (1948)
Shipton (1943)
Evans (1956)
Ward (1968)
Messner(1979, p. 137)
Clarke (1983)
Asajiefo/. (1984)
Jenzerand
Bartsch (1993)
Sharmarto/. (1990)
Jenzerand
Bartsch (1993)
Murdoch (1994)
Murdoch (1994)
Murdoch (1994)
Basnyat(1997)

brain tumor have become symptomatic at altitude

(Shlim and Meijer 1991).
The term high altitude global amnesia (HAGA)
has been used by Litch and Bishop (1999, 2000) to
describe a variety of neurological features associated
with transient loss of memory and confusion but not
associated with obvious HAPE. As the cerebral cortex
is vulnerable to hypoxia, local hypoxia of the limbic
cortex may be implicated. Cases of HAGA, rectus
palsy and TIA may be commoner than realized.
There are many anecdotal accounts, but few cases are
recorded in detail (Murdoch 1996). In Operation
Everest III (Comex), a 40-day chamber study of eight
subjects, there were three cases of TIA towards the
end of the study at an altitude equivalent of above
8000 m. They all recovered rapidly (Richalet et al
1999).

of 4300 m were reported by Hackett et al. (1987c), four

on Denali in Alaska and two at Pheriche near Everest.
These individuals were not suffering from pulmonary
edema or severe AMS. They did not have retinal hemorrhage. The blindness lasted from 20 min to 24 h,
with intermittent periods of normal vision. Oxygen
breathing relieved it and recovery was complete. It was
thought to be due to hypoxia or ischemia of the visual
cortex. Houston (1987) also reported various visual
disturbances on acute exposure to altitude in chambers. There is some suggestion that subjects with a history of migraine are more susceptible and that aspirin
may help prevent attacks, which may be related to
platelet aggregation and microemboli.

22.2.2 Cortical blindness and transient

visual defects

There has been considerable interest in factors in the

blood associated with clotting, and the effect of
hypoxia, with and without symptoms of AMS, on
these systems. This is because of the frequent finding
of thrombi in various organs at postmortem in cases

Transient blindness has been reported in otherwise

healthy individuals at altitude. Six cases at an altitude

223

PLATELETS AND CLOTTING

262 Other altitude related conditions

of AMS and its complications (Dickinson et al.

1983), and the frequency of cases of cerebrovascular
accidents at altitude.

223.1

Platelet counts

In mice, there is a profound fall in platelet count on

exposure to hypoxia. Counts are down to 36 per cent
of control by day 12 (Birks et al. 1975). In humans,
no such fall has been found. It has been reported that
in the first few days there is either no change (Maher
et al. 1976, Sharma 1982), or a small fall of 3 per cent
in subjects with AMS and a rise of 3 per cent in
asymptomatic subjects (Sharma 1980). Chatterji et
al. (1982) found a 12-26 per cent reduction in
platelet count on day 2 or 3 at altitude in two studies
at 3200 m and 3700 m. Counts increased towards
control values over the next 10 days. These small
changes may simply reflect hemoconcentration or
dilution. With more prolonged exposure Sharma
(1981) found a 14 per cent increase by 21-31 days
followed by a fall to sea level values at 180 days. At
4300 m, a rise of between 50 per cent and
100 per cent has been found, both on arrival and
2 weeks later, after climbs to higher altitude (SimonSchnass and Korniszzewski 1990).

223.2

Platelet adhesiveness

Under a variety of conditions platelets become more

sticky, and this property may be important in initiating platelet thrombi. Sharma (1982) has also studied
the effect of altitude on platelet adhesiveness. On
acute exposure to altitude he reported an increase in
platelet adhesiveness in subjects with AMS, compared with their sea level results. However, this was
only on days 2 and 10 of altitude exposure and not on
days 1 and 4. Also, the sea level values for symptomatic subjects were markedly less than for the
asymptomatic group. Actual values at altitude were
the same for both groups. He also reported (with
others) that high altitude residents had significantly
higher platelet adhesiveness than lowlanders at sea
level (Sharma etal 1980).

2233

Coagulation

Singh and Chohan (1972a) found an increase in

fibrinogen level and fibrinolytic activity in 38 sub-

jects at altitudes between 3670 m and 5470 m, but, in

six subjects thought to have pulmonary hypertension
on clinical grounds, the fibrinogen levels were lower,
suggesting consumption coagulopathy. In these
patients, factors V and VIII were increased, as was
platelet factor III. Maher etal. (1976) also found a fall
in fibrinogen level in eight subjects in a simulated
altitude of 4400 m but no change in thrombin or
prothrombin times; platelet factor III was normal.
Partial thromboplastin time was shortened and factor VIII activity was reduced. Hyers et al. (1979)
found accelerated fibrinolytic activity in subjects
with and without susceptibility to AMS but no
change in fibrinogen, partial prothrombin time,
platelet lysis time or fibrinopeptide A. In patients
with HAPE, fibrinogen levels and venous clot lysis
time have been reported to be increased (Singh et al.
1969a, Singh and Chohan 1972a).
Bartsch et al. (1982) showed, in 20 subjects taken
rapidly to 3700 m, that there were no changes in
coagulation tests 1 h after arrival. After strenuous
exercise there was shortening of clotting time,
euglobulin lysis time, and increase in factor VIII
activity - changes that are all found on exercise at sea
level. There was no change in fibrinopeptide A and
no rise in fibrin degradation products or fibrin fragment E (i.e. no evidence of intravascular clotting). In
a later project the contact phase of blood coagulation
was studied in subjects who had ascended to 4559 m
in 3 days. There was no evidence of activation of this
system even in subjects who developed acute HAPE
(Bartsch etal. 1989).
An extensive study of the clotting cascade during a
40-day chamber experiment, Operation Everest II,
when subjects were taken in stages up to the simulated equivalent altitude of Mount Everest, showed
no significant changes in clotting factors, though
thrombosis round the sites of Swan-Ganz catheters
was common (Andrew et al. 1987).
In summary, it seems that the physiological
response to hypoxia has not been shown to involve
any important changes in platelet count or adhesiveness or in other clotting factors. However, there may
be changes associated with AMS and especially
HAPE (Singh and Chohan 1972b). These may
include changes suggesting disseminated intravascular coagulation but this is still not proved. The
changes so far demonstrated seem to appear rather
too late in the course of altitude exposure to be considered causative, so, even if present, they may repre-

Case histories 263

sent an effect or a complication of AMS rather than

being essential in its genesis.

22.4

SPLINTER HEMORRHAGES

Splinter hemorrhages may occur under the fingernails of high altitude natives, and are more pronounced in those with CMS and in climbers at
extreme altitude (English 1987). In South American
high altitude dwellers, the incidence appears to
increase with altitude, rising from 34.9 per cent at
150 m to 57.9 per cent at 4200 m (Heath and
Williams 1995, pp. 311-13). In over 1000 healthy
Chinese children born at altitude, examination of the
nails showed an increase in number of capillary loops
and abnormal loops (Han et al. 1985). The cause of
these hemorrhages may be associated with increased
capillary fragility or it may be embolic or traumatic
in origin.

22.5

RISK FACTORS FOR THROMBOSIS

The risk factors for thrombosis include decreased

physical activity, dehydration, increased hematocrit
and cold.
Physical activity may be greatly decreased at altitude. Individuals may spend several days recumbent
in a sleeping bag in bad weather and, even in good
weather, activity can be restricted by fatigue to a
shorter working period each day than at lower levels.
Dehydration is common, with increased respiratory water loss owing to cold and a high respiratory
rate. A diminished sensation of thirst, together with
the practical difficulties of melting snow to produce
water, results in an inadequate fluid intake.
A hematocrit of 45-60 per cent is normal for sea
level visitors to altitude and some high altitude residents. When the hematocrit exceeds 50 per cent the
apparent viscosity increases steeply. Vasoconstriction further increases viscosity and thus cold will contribute (Whittaker and Winton 1933, Pappenheimer
and Maes 1942). Cold can also damage vessel walls
and by causing coronary vasoconstriction may be
implicated in 'heart attacks'. Cerebral venous thrombosis has been reported (Fujimaki et al. 1986, Song et
al 1986).

22.6
MECHANISMS OF VASCULAR
ACCIDENTS
The mechanism of vascular accidents is debatable.
Short-lived attacks may be due to spasm, or possibly
a manifestation of migraine. Thrombosis is another
possibility, due to a high hematocrit and dehydration
(Ward 1975, pp. 289-92), and disturbances of coagulation and platelet function may also occur. In some
cases hemorrhage cannot be ruled out. As with
'stroke' at lower altitudes, there may be different
causes. However, the risk of a cardiovascular accident in an otherwise fit person at altitude, though
small, would appear to be greater than would be
expected from such a population at sea level.
22.7
22.7.1

CASE HISTORIES
Patient A

A white man, aged 32, while climbing at 8400 m, suddenly experienced a severe pain in the right side of
his chest and collapsed. He was unable to move for
30 min and then started to cough up dark red blood.
After a night at 8200 m he crawled down to a lower
camp at 7800 m, continuing to complain of severe
pain and coughing up blood.
Three days later, that is, 5 days after the initial incident, he reached camp at 7800 m. He was barely conscious and his feet and hands were gray-white in
color and had the consistency of wood. He was evacuated to a camp at 6400 m where his general condition was poor and he was still coughing up blood. On
examination, air entry at the base of the right lung
was found to be greatly diminished, and there was
deep frostbite to both legs below the knees, but both
popliteal and femoral arteries were palpable. Deep
frostbite was also present in the distal parts of all fingers and both thumbs.
In the next 2 days he was evacuated to 4600 m and
then flown to hospital at 1100 m. Here a chest radiograph showed shadowing in the right lower zone,
presumably an infarct. Later he developed a lung
abscess in this part of the lung and then an empyema
with bronchopleural fistula. After a rib resection and
drainage this resolved (Figures 22.1-22.3).
Eventually, bilateral below-knee amputation was
carried out and all fingertips on both, hands were

264 Other altitude related conditions

Figure 22.1 Patient A: thrombosis of the right lower lobe, which

occurred at 8350 m.
removed after mummification. There remained
some scarring of the right hand with restriction of
finger and thumb movement (Ward 1968).

22.7,2

Patient B

A white man climbed from 7850 m to 8750 m in 13 h

using supplementary oxygen and then spent 35 min
on the summit. He bivouacked for the night a few
hundred meters lower. The night temperature was
estimated at -30 C with winds gusting to
80-95 km Ir1 (50-60 mph). During the night his
supply of oxygen ran out and he shivered continuously. Later he estimated that he had had nothing to
drink for 30 h while above 7900 m.
Next day he descended and developed a persistent
cough. A day later he complained of pain in the left
side of his chest and, when examined, was told that he
had pneumonia and pleurisy. He continued to have
chest pain and then 4-5 days later began coughing up
blood. Eleven days after he had reached the summit,
chest radiograph showed a left pleural effusion. Three
days later he was admitted to hospital in the USA. Six
weeks after the initial incident, at operation, a fibrous

Figure 22.2 Patient A: after the development of a right pleural

effusion.
tissue mass occupying 50 per cent of the lower half of
the left thorax was excised. He made an uneventful
recovery and postoperatively reached an altitude of
5800 m. His stamina has in no way been impaired
(Wickwire 1982).

22.73

Patient C

A white man, aged 40, complained of severe

headache at 6400 m. This continued for 3 days and
was relieved by codeine tablets. By the evening of the
third day he noticed that he could not speak properly. On examination he had nominal aphasia but
could understand the spoken word. There was some
evidence of right facial weakness with involuntary
movements confined to the right side of the face.
Both carotid arteries were palpable. There was loss of
power in the right arm, but no loss of sensation. The
lower limbs could not be examined as the patient was
in a sleeping bag.
After sedation and continuous oxygen by mask for
8 h, he was able to descend to 5000 m, with some
difficulty due to weakness of the arms and legs. For a

Retinal hemorrhage 265

calves are constricted, may lead to the formation of

'silent' calf thrombosis. Regular movement is therefore important. In subjects with an abnormally high
hematocrit (e.g. over 0.65), after adequate hydration,
venesection should be considered if the subject plans
to remain at altitude. Hemodilution has been used
for treating polycythemia in mountaineers; it is considered to be a potentially hazardous maneuver
(Sarnquistefa/. 1986).

22.8.2

Figure 22.3 Patient A: After the development of a right

pyopneumothorax and bronchopleural fistula.

further 3 days speech remained slurred, he was often

at a loss for a word and individuals' names were
mixed. After 15 days there were no residual signs; a
note written at this time contained lucid statements
and logical arguments and his writing was normal.
There appeared to be no permanent after-effects
(Ward 1968).

22.8

22.8.1

MANAGEMENT

Prevention

Adequate hydration is extremely important and, as

the majority of mountaineers at extreme altitudes
appear to be dehydrated, the danger of thrombosis
occurring probably increases with length of stay.
Posture too may be significant, particularly while
bivouacking, when a fetal position is assumed to prevent too much heat loss. As the knees, hips and arms
are kept flexed there is an increased risk of thrombosis, so arm and leg stretching should be carried out
regularly. Lying in a sleeping bag, particularly if the

Treatment

Treatment will depend upon the diagnosis but all

patients will benefit from descent and hydration.
Oxygen may improve those who are severely
shocked. Anticoagulants are potentially dangerous
and adequate laboratory facilities should be available
before they are used. However, in exceptional circumstances in cases of thrombosis and if the physician is experienced, small doses of a short-acting
anticoagulant may be given. Return to altitude after a
vascular episode should be considered with caution,
but some have returned with future expeditions to
climb at high altitude without recurrence of symptoms.

22.9
22.9.1

RETINAL HEMORRHAGE
Clinical features

In 1970 Frayser et al. reported retinal hemorrhages in

35 per cent of subjects flown to 5330 m. Since then
retinal hemorrhages have been found in a proportion
of climbers on a number of expeditions (Rennie and
Morrissey 1975, Clarke and Duff 1976). The condition is almost always symptomless and self-limiting.
The hemorrhages are usually multiple, often flame
shaped and adjacent to a vessel. If near the disc there
maybe some blurring of vision.
Besides hemorrhages, 'cottonwool' spots have
been reported in one case (Hackett and Rennie 1982)
and some mild papilledema may be present as well.
There is usually engorgement of both arteries and
veins (Figure 22.4).
The hemorrhages are usually found during the first
few days after ascent to altitude (the 'at risk' time for
AMS) and subjects are often suffering from AMS,
though the correlation with severity of AMS is not

266 Other altitude related conditions

increased by 105 per cent (Frayser et al. 1970).

Rennie and Morrissey (1975) found arterial diameter
to be increased by 24 per cent and venous diameter
by 19 per cent. They suggest that, in the presence of
these dilated vessels, the sudden rise in vascular pressure associated with coughing and straining may
cause a microvessel to rupture; cough is common
and severe at altitude (see section 22.11). However,
Sakaguchi and Yurugi (1983) have produced retinal
hemorrhage in monkeys in a chamber when presumably cough was absent. In 16 exposures 5 monkeys
showed retinal hemorrhage, whereas no retinal hemorrhage was produced in 46 rabbits. The authors
point out that rabbits, unlike monkeys or humans,
have arteriolar-venular anastomotic vessels in their
retina, which may protect them.

22.10 ALTITUDE AND CORNEAL

SURGERY

Figure 22.4 Retinal hemorrhage at altitude.

strong (Rennie and Morrissey 1975). A recent study by

Wiedman and Tabin (1999) found a significant correlation between retinopathy and HACE (p = 0.02).

22.9.2

Incidence of retinal hemorrhage

The incidence varies from zero on one 10-member

expedition to Mount Kongur (7719 m) in Xinjiang,
to 15 of 16 members on an expedition to Peak
Communism (7495 m) in Russia (Nakashima 1983).
It seems that people going to altitude for the first
time are especially liable to show this phenomenon
(Clarke and Duff 1976) whereas experienced high
altitude climbers and Sherpa residents are relatively
immune. Wiedman and Tabin (1999) found
retinopathy in 19 of 21 climbers who went to over
7500 m and in 14 of 19 who ascended to between
5000 and 7500 m.

22*93 Mechanism of retinal

hemorrhage
At the time when retinal hemorrhage appears, the
cerebral blood flow is increased (Severinghaus et al.
1966a). The blood flow through the retinal vessels is

22.10.1

Hypoxia and the cornea

The cornea relies on the direct diffusion of oxygen

from the air for its oxygen supply. At altitude it
therefore suffers from hypoxia but, unlike other tissues in the body, there can be no compensatory
mechanisms of acclimatization such as increased
ventilation and hemoglobin concentration. The
effect of hypoxia on the cornea is to increase its
hydration, causing it to swell. Shutting the eyes as in
sleep results in lowering the P02 further so that any
swelling will be worse after a night's sleep. Normally
this swelling is not noticed and causes no change in
the refraction of the eye in either normal eyes or
myopia (short sight).

22.10.2

Surgery for myopia

A number of operations have been devised to change

the refraction of the cornea in myopia, one of the
most successful and frequently performed being
radial keratotomy (RK). Millions of young people
have now benefited from this operation. In this operation four to eight radial incisions are made in the
cornea from the edge of the central area to the
periphery. The effect of this maneuver is to cause a
flattening of the cornea as the incisions heal and contract, reducing the power of the cornea/lens system

High altitude cough 267

and thus correcting much or all of the refractive error

of the eye. Originally the incisions were made by a
diamond scalpel but now a laser is usually used.
Another operation is photorefractive keratectomy
(PRK). Here a laser is used to ablate and remodel the
anterior surface of the cornea, reducing its curvature.

22*103 Hypoxia and the postsurgical

myopic patient
Mader and White (1995) and Mader et al (1996) have
studied the effect of hypoxia on subjects following
surgery. In the first study four normal corneas were
compared with four which had undergone RK at
12 000 ft (3658 m) and 17 000 ft (5182 m) for 24 h.
They found that from sea level to 12 000ft there was a
change in refraction of the operated eyes of -0.59
diopters and at 17 000 ft of-1.75 diopters after 24 h.
There was no change in the normal eyes. In the second
study at 14 100ft (5182 m), six subjects with RK, six
with PRK and nine with myopia were studied daily for
3 days. There was no change in refraction in the subjects with myopia or PRK, whereas the RK subjects
had significantly changed refraction. The mechanism
of this change is probably due to the swelling of the
cornea because of hypoxia causing further flattening
of the RK cornea. The effect is to make the subject farsighted. These changes are all reversible after return to
sea level. However, although the changes at moderate
altitude are probably only of nuisance value, at
extreme altitude they can result in near blindness
which in turn can lead to catastrophe as in the case of
an American climber on Everest in 1996 (Krakauer
1997). If subjects who have had RK wish to climb high
they should be advised to take a selection of cheap
positive lens glasses to correct the change in refraction
that can be expected. It is not possible to predict this
change accurately.
22.11
22.11*1

HIGH ALTITUDE COUGH

Background

It has been common knowledge amongst mountaineers that cough is a problem at high altitude,
especially after some time spent at extreme altitude.
Tasker writes in his account of the winter expedition
on Everest's west ridge:

Alan (Rouse)... was still racked by frequent coughs

and periodically, as if by auto-suggestion I found
that I too was succumbing to a bout. Once started,
there was no escape. The cold dry air compounded
the irritation in the throat and the victim's body
would be shaken by the hacking cough until randomly flung free of its spell. The nights at Base
Camp as well as on the mountain were often punctuated by staccato bursts of noise disturbing the
sleep of the sufferer and all those around (Tasker
1981).

Apart from disturbing the sleep of climbers, cough

is quite debilitating and can even cause rib fracture
(Steele 1971).
Although well known to climbers, altitude cough
attracted no scientific study until Barry and colleagues carried out their work on the British Mount
Everest Medical Expedition (BMEME) in 1994. They
first documented the reality of increasing cough frequency with altitude and length of stay. They did this
by using voice-activated tape recorders and showed
that the number of coughs at night increased from
zero at sea level to a mean of 60 per night at 7000 m
(Barry etal. 1997a).

22.11.2

Mechanism

It has been generally assumed that the cause of altitude cough is the cooling and drying of the upper airway due to hyperventilating cold, dry air at altitude.
However, anecdotal reports of cough in long-term
chamber studies such as Operation Everest II, where
the temperature and humidity were controlled at
comfortable levels, gave pause for thought as to
whether this was the whole story. In Operation
Everest III (COMEX '97) cough frequency was monitored, again with voice-activated tape recorders, and
shown to increase with altitude (Mason et al. 1999).
In 1994 Barry and his team also measured the cough
threshold to citric acid. In this test the subject is given
a nebulizer of increasing concentrations of citric acid
and the concentration which first provokes cough is
noted. This threshold was reduced at altitude (Barry
et al. 1997a). In the Operation Everest III study the
cough threshold for citric acid also was shown to
decrease at 8000 m even though the temperature
was kept at 18-24C and relative humidity at
30-60 per cent
Barry et al. (1997b) also documented a decrease

268 Other altitude related conditions

in mucociliary clearance by the saccharin time test

and also found that the sensation of nasal blockage
was increased at Everest Base Camp. In a doubleblind, placebo-controlled trail on Kangchenjunga in
Nepal in 1998, the same team showed that salmeterol or nedocromil could prevent the reduction in
cough threshold, though the effect on cough frequency was not significant (Bakewell et al. 1999).
Also it was shown, in a controlled trial, that moistening the nasal mucosa by saline spray four times a
day prevented the increase in saccharin times seen
in the control group.
It is probably too early to make a coherent hypothesis taking into account the results of all these studies. It is apparent that altitude cough is not simply an
effect of cold dry air and hyperventilation, though
these may be factors. Results from chamber studies
suggest that hypoxia per se is at least a factor. The
importance of the changes in the nasal mucosa is also
not clear. Finally, combining results of two separate
studies from BMEME '94 showed that those individuals who had the greatest change in cough threshold
also had the greatest increase in dynamic carbon
dioxide ventilatory response (see section 5.16)(Barry
et al 1997c). This is in line with an earlier finding by
Banner (1988) of a correlation between cough
induced with hypotonic aerosol and the ventilatory
response to carbon dioxide. This raises the possibility
that central mechanisms may be involved.

22.12

22*12.1

ANESTHESIA

Summary

A considerable number of major medical centers are

at altitudes of 1500-2000 m. General anesthetics are
administered there safely, and with only minor modifications of techniques. Above 2000 m, increasing
attention must be paid to the effects of decreased
barometric pressure. Anesthetics are not normally
administered above 4000 m, and the response to general anesthesia in this situation has not been systematically studied. Anesthesia above this altitude might,
however, be required in an emergency and is potentially very dangerous This is because anesthesia abolishes the peripheral chemoreceptor response to
hypoxia. This, together with the low PI02> means that
the patient is at serious risk of severe hypoxia. The

use of intravenous ketamine with oxygen enrichment

may be the technique of choice but local anesthetic
is considered safer at altitude (Stoneham 1995).
Patients requiring general anesthetic should,
wherever possible, be evacuated to lower altitude.

22.12.2

Avoidance of hypoxia

During anesthesia with spontaneous ventilation,

breathing is almost always depressed and alveolar
ventilation may be reduced to half the value appropriate to the metabolic rate. Whether breathing is
spontaneous or artificial, there is usually an increase
in the alveolar/arterial P02 gradient, equivalent to a
shunt of about 10 per cent of pulmonary arterial
blood flow. For these reasons maintenance of a
normal arterial P02 requires, at sea level, an increase
in the inspired oxygen concentration to 35-40
per cent. The inspired P02 is thus about 300 mm Hg
and this should be maintained regardless of barometric pressure. The concentration of oxygen
breathed by the anesthetized patient should therefore be increased in accordance with altitude, as
shown in Table 22.2.
Nitrous oxide is an effective anesthetic at an alveolar partial pressure of about 750 mm Hg (70 per cent
nitrous oxide at sea level is only a partial anesthetic).
It will be clear from Table 22.2 that it cannot make a
very effective contribution to anesthesia above
2000 m, at which altitude only 46 per cent of the
inspired gas is available for nitrous oxide. It is contraindicated at any higher level and general anesthesia must then be based on potent volatile anesthetic
agents vaporized in oxygen enriched mixtures.
Intravenous anesthetics should only be used with
oxygen enrichment of the inspired gas according to
Table 22.2.
Table 22.2 Minimal concentrations of oxygen in the
inspired gas required to maintain a normal arterial ?02 in
the anesthetized patient

Sea level
2000
4000
6000

760
596
462
354

40
54
72
100

285
296
298
307

PB, atmospheric pressure; PI0, partial pressure of inspired oxygen.

Anesthesia 269

22.123

Hypoxic ventilatory drive

Survival at altitudes much in excess of 5000 m

depends upon hyperventilation in response to
hypoxic drive, although this is counteracted by negative feedback, resulting from reduction of the PC02. It
is now established that anesthesia (and even subanesthetic concentrations of anesthetics) will totally
abolish the peripheral chemoreceptor response to
hypoxia (Knill and Celb 1978). It is therefore possible to envisage a situation in which a patient at
6000 m, who would normally have an arterial P02 of
45 mm Hg and a PC02 of 23 mm Hg, might perhaps
be anesthetized with halothane and air. There would
be rapid inactivation of peripheral chemoreceptors
with decrease of P02 to about 23 mm Hg, which
would threaten life. An increased oxygen concentration is therefore essential, not only during anesthesia,
but in the postoperative period, because the peripheral chemoreceptors are severely depressed by as
little as one-tenth of the anesthetic concentration of
volatile anesthetic agents.

22.12.4

Performance of vaporizers

Calibrated vaporizers depend upon known dilution

of saturation concentrations of volatile anesthetics.
The saturation concentration equals the vapor pressure divided by the barometric pressure. Vapor pressure depends only on temperature. Thus, if the
barometric pressure is halved, the saturation concentration is doubled. If the dilution ratio of the vaporizer is unaffected by the reduction in barometric
pressure (a reasonable assumption), it may be
expected that the vaporizer will then deliver twice the
concentration shown on the dial. However, the
pharmacological effect depends on partial pressure.
Twice the concentration at half the barometric pressure gives the same partial pressure as at sea level.
Therefore, as a first approximation, probably
adequate for clinical purposes, a temperature controlled calibrated vaporizer may be expected to
produce the same effect for the same dial setting at
altitude as at sea level.
These concepts have never been tested at altitude.
However, one of the authors (MPW), Nunn and
Woolmer anesthetized one another in a chamber at a
pressure of 375 mmHg in 1961, in preparation for
the Himalayan Scientific and Mountaineering

Expedition (Silver Hut) 1960-1. The apparatus was

based on equipment designed for use in Antarctica
(Nunn 1961). With a carrier gas of 60 per cent oxygen in nitrogen, obtained with oxygen flow through
an injector, and a standard halothane vaporizer
(Fluotec Mark 2), uneventful anesthesia was easily
obtained in all three subjects and recovery was rapid
and uneventful. In view of the subsequent discovery
of the effect of anesthetics on the peripheral
chemoreceptors, we would now favour 100 per cent
oxygen at this simulated altitude of nearly 6000 m.

22.12.5

Practical considerations

The greater the altitude the lower is the possibility of

a trained anesthetist and appropriate equipment
being available. Dangers are multiplied by anesthesia
being attempted in this very hostile environment by
someone who is untrained. The first rule must be to
avoid anesthesia above 4000 m if at all possible and to
evacuate rather than attempt surgical intervention
on the spot.
If anesthesia is essential, then oxygen enrichment
of the inspired gas is essential for both patient and
anesthetist throughout the perioperative period. The
safest technique is probably a nonirritant volatile
anesthetic (halothane, enflurane or isoflurane)
vaporized in oxygen-enriched air according to Table
22.2. It was demonstrated that this technique could
be accomplished at sea level by medical officers without special training in anesthesia who were destined
for the Antarctic (Nunn 1961). Transport of sufficient oxygen, the vaporizer and the gas delivery
system would clearly present logistic difficulties. Use
of the open mask is not recommended because of the
difficulty in controlling the inspired oxygen concentration. Ruttledge (1934) described a near disaster
when chloroform was administered on an open mask
at 4300 m on the Tibetan plateau during the march
in on the 1933 Everest expedition. This would be
expected on present understanding.
Intravenous anesthesia should not be attempted at
altitude by those without experience because of the
dangers of respiratory obstruction and depression.
However, ketamine (2-4 mg kg"1) might well be satisfactory because the patient's airway and respiratory
drive are well maintained with this drug. This is logistically very attractive for major disasters, mass casualties and warfare. There is good analgesia, and duration

270 Other altitude related conditions

is sufficient for any procedure likely to be considered.

Hallucinations may occur but would be the least of the
patient's problems. Ketamine should only be administered with oxygen enrichment. A study of the use of
ketamine anesthesia at 1850 m without supplementary
oxygen found that saturation values fell below
90 per cent in significant numbers of patients, particularly in adults. However, the authors conclude that
ketamine was acceptable provided that supplementary
oxygen and staff experienced in airway management
were readily available (Pederson and Benumof 1993).
A recent report from Khunde Hospital (3900 m) in
Nepal describes the successful use of ketamine in 11
cases. A low dose (2.0 mg kg"1) was used and premedication with midazolam prevented the nightmares
commonly encountered with ketamine. Oxygen saturation was maintained either with supplemental oxygen or by encouraging the patient to breathe faster and
deeper (Bishop etal 2000).
Reliance on injectable solutions must be tempered
by the hazard of freezing and breakage of ampoules.
Local anesthetic techniques are obviously safer and
should be used if at all possible in preference to general anesthesia at altitude.

22.12*6

Postanesthetic period

In the postanesthetic period, after a general anesthetic, the hazard of hypoxia due to respiratory
depression discussed above is still very real. Indeed,
in the hours after the operation, the danger may be
greater since the patient may not be so closely
watched as during anesthesia.
It should be remembered that, even at sea level,
patients are normally mildly hypoxic during this
stage. Hypoxia may cause restlessness, irritability
and confusion, which may be misinterpreted as
being due to pain. Additional analgesics may then
be administered which further depress respiration
and the patient may die from hypoxic cardiac
arrest. This was probably the sequence of events in
a Sherpa operated upon for debridement of
frostbitten fingers at an altitude of 3900 m.
Clearly, supplementary oxygen must be given during the postanesthetic period if available. The
patient must be closely watched and stimulated to
breathe either by verbal encouragement or, possibly, by the use of a respiratory stimulant such as
doxapram.

23
Thermal balance and its regulation
23.1

General principles

23.2
23.3
23.4
23.5

Regulation of core temperature

Thermal balance
Cold-induced vasodilatation
Thermal exchange

23.6

Regulation of body temperature

271
272
272
273
273
276

SUMMARY
To maintain cell function, the core temperature
must be kept between 36 C and 38 C and this
enables humans to be almost independent of the
environmental temperature. The price paid is a
relatively high metabolic rate. The regulation of core
temperature depends on physiological and cultural
mechanisms, whereas thermal exchange relies on
convection, conduction, radiation and evaporation.
At high altitude the balance between heat production
and loss is tilted, because of hypoxia, towards poor
heat production and increased loss. Indeed,
hypothermia and frostbite can occur despite subjects
being fully clothed and mobile. Solar radiation may
be critical in preventing hypothermia. Clothing
insulation is of great importance, but malnutrition,
fatigue, food and fluid intake also all influence
temperature regulation.

23.1

GENERAL PRINCIPLES

For the past 70 million years mammals (homeotherms) have developed a system of temperature
regulation which keeps the core temperature
between 36 C and 38 C to maintain cell function.

23.7

Heat production

277

23.8
23.9
23.10
23.11

Heat loss
Heat conservation
Thermal balance at high altitude
Factors altering temperature regulation

277
278
282
282

This enables them to be almost independent of the

temperature of the environment, which may vary
from +40 C to -40 C, and is therefore of considerable evolutionary advantage. The price that is paid is
a relatively high metabolic rate compared with
poikilotherms, or cold-blooded animals, whose core
temperature is more closely allied to that of the
environment.
To maintain cell function, the core temperature of
humans has to remain within a narrow band, though
small variations occur during the menstrual cycle,
the circadian rhythm and fever. A core temperature
higher than 41C (hyperthermia) or lower than
35C (hypothermia) may cause death.
The relationship between heat production by the
body and heat loss to the environment obeys two
physical laws.
Fournier's law states that the rate of heat transfer
between an object (or animal) and the
environment is proportional to its surface area
and the difference in temperature between the
body and the environment. As all living
organisms produce heat by metabolism and since
heat flows from a hot to a cold object, all living
animals that usually have a higher body
temperature than the environmental temperature
will therefore lose heat to the environment.

272 Thermal balance and its regulation

When heat production is exactly balanced by

heat loss a steady-state temperature will have
been achieved. As poikilotherms have no control
mechanisms to alter the relationship between
heat loss and heat production, their metabolic
rate, body temperature and activity will be
dependent on the environmental temperature.
Arrhenius's law, put simply, states that, as
temperature increases, so does the metabolic rate
and therefore the rate of heat production.

23.2
REGULATION OF CORE
TEMPERATURE
Two main mechanisms regulate core temperature
and keep it at 37 C. There are physiological or reflex
mechanisms, which are involuntary, and behavioral
mechanisms, which are voluntary.
23*2.1

Physiological mechanisms

PHYSICAL

Physical mechanisms include vasomotor control,

which can alter blood flow to the skin by a factor of
more than 100, and sweat production. In the cold,
to reduce heat loss from the periphery, blood is
shunted from the surface to the deeper vessels.
Conversely, as the ambient temperature rises, so
more blood flows through the surface vessels to
dissipate heat.
When the ambient temperature is higher than the
temperature of the body surface, and heat loss by
radiation, conduction and convection is not possible,
then active sweat production starts and heat is lost by
evaporation.
Thus by physical means alone humans can tolerate
a wide range of environmental temperatures and still
maintain a constant core temperature.
CHEMICAL

Chemical mechanisms enable adjustments of

metabolism to be made by hormonal and neural
methods. These come into play when physical
methods have been overtaxed, for example when
maximal vasoconstriction has taken place but heat
loss remains larger than heat production.

First, muscle tone is increased, then muscle

tremors occur and finally shivering starts. Intense
shivering can raise the metabolic rate by three to four
times the basal level. Heat is produced very efficiently
as no external work is done and virtually all the
energy from contraction is produced as heat within
the muscle. In addition, nonshivering thermogenesis
can increase basal metabolism by 30-40 per cent.
In humans, therefore, physiological mechanisms
alone are capable of maintaining a constant core
temperature at widely varying environmental
temperatures.
23.2.2

Behavioral mechanisms

Behavioral mechanisms include all voluntary

actions that make the individual thermally comfortable. In hot conditions, taking cold drinks, seeking
the shade, and air conditioning are common; in
cold climates extra clothing is worn, exercise is
increased, and the individual stays indoors and
lights a fire.
These mechanisms give us the greatest independence from the environment and, through our
ingenuity and the application of modern technology,
we can survive in the hottest, coldest, deepest and
highest places on Earth and even in space.

23.3

THERMAL BALANCE

A useful but oversimplified concept is to imagine the

body as consisting of a central core at a fairly uniform
temperature of 37 C, with some organs such as the
liver at 1-2C higher, and an insulating shell some
degrees lower. The body is therefore continually
losing heat and in a cold environment has to
maintain a balance between heat production and
heat loss (Burton and Edholm 1955). In reality there
is no physical or anatomical boundary separating the
central core from the insulating shell and the difference can be thought of in terms of the temperature of
the tissues.
In hot weather, or during periods of increased
exercise, some heat loss is necessary to maintain
thermal balance, and the core is enlarged,
extending into the root of the extremities.
During exercise most heat production occurs in

Thermal exchange 273

the proximal muscles of the limbs and the skin

vessels are dilated to bring warm blood to the
skin surface to lose heat; as a result the insulating
shell is thin.
In a cold climate, or when heat production falls
and it is important to conserve heat, skin vessels
contract and venous return is confined to the
deeper vessels. The core decreases in size and is
restricted to the head, neck, thorax and
abdomen, and the thickness of the insulating
shell increases. As blood flow to the skin can be
increased to 100 times that of normal by
vasomotor activity, and as much of the transfer
of heat in the body is by convection via the blood
flow, this is a very important method of heat
conservation.
As well as vertical temperature gradients between
skin and vessels there are also longitudinal gradients
down the length of the limbs where countercurrent
heat exchange takes place between the arteries and
veins.

23.4

COLD-INDUCED VASODILATATION

The object of thermal regulation is to maintain the

central core temperature at 37 C and, if the environmental temperature falls, the body will 'sacrifice' the
extremities to maintain the core, but it does put up a
considerable fight to maintain the temperature of the
extremities. To this end, under certain conditions
and in some individuals only, the extremities exhibit
the phenomenon of cold-induced vasodilatation.
When this occurs the normal response to cold, which
is peripheral vasoconstriction to reduce blood flow
and heat loss, is reversed, and vasodilatation occurs.
Warm blood flows to the periphery and the temperature is raised. This surge is transient only and
vasoconstriction then sets in. The mechanism is not
certain but, although it could be central in origin, the
neural mechanism for vasoconstriction may be
inhibited by local cooling causing the vessels to relax.
The magnitude of the heat input to the extremity
caused by cold-induced vasodilatation is small and
cannot prevent frostbite at below-zero temperatures,
or nonfreezing cold injury, but it may result in less
finger pain when working in cold conditions
(Hoffman and Wittmers 1990).

23.5

THERMAL EXCHANGE

The body is continually losing heat to the environment and heat exchange occurs by convection,
radiation, conduction and evaporation.
23.5.1

Convection

Convection is a molecule-to-molecule transfer of

energy. The medium accepting heat is either a gas in
motion or a fluid. Although the thermal conductivity
and heat capacity of a gas may be low, its movement
ensures a high thermal gradient between the body
and the environment. The wind chill factor describes
the increased heat loss by convection due to air
movement, either by wind or body movement.
Convection is also an important avenue of heat
exchange during immersion in water; even in still
water it is 26 times that of air. Heat transfer within
the body is by convection, that is, by the flow of
blood, which is a factor of great physiological
importance.
In a cold environment warm air currents are
generated adjacent to the skin and slowly rise to be
replaced by cold air, which in turn is heated at the
expense of body temperature. The rate of convective
heat exchange depends on the amount of exposed
skin surface area (which is almost always less than the
total body surface) and the extraneous air movement, which will accelerate the movement of warm
air currents; this is so-called 'forced convection'.
Posture is important and the surface area may be
reduced by curling up in the fetal position, which is a
behavioral response. The heat required to maintain a
constant internal temperature is heavily dependent
on the body mass/surface area ratio. The heat loss
from a squat individual is significantly less than from
a tall, thin person of the same weight. Children have
a particularly unfavorable ratio and easily become
hypothermic.
WIND AND WIND CHILL
An important influence on the rate of heat exchange
by convection is the wind. Forced convection, either
by wind or by relative air movement (e.g. downhill
skiing or riding in open vehicles), is a major cause of
heat loss in a cold environment; this is known as
wind chill.

274 Thermal balance and its regulation

Wind chill correlates the effects of wind and

temperature and provides an index which corresponds to the degree of discomfort that is experienced
in the field (Siple and Passel 1945). This effect can be
quantified by quoting the equivalent still air
temperature produced by any given wind speed. This
is shown in Table 23.1. For instance, at a temperature
of-l 0 C the effect of a 10 mph (16 km Ir1) wind on
the skin is equivalent to a still air temperature of
-9C.
Under field conditions, however, the tolerance of
humans to cold and wind is determined by those
parts that are unprotected, often the face and hands.
Exposing the face when walking into the wind is less
tolerable than walking at an angle and with some
protection.
The chilling power of the wind can produce
extreme cooling of the skin and, without protection,
frostbite of the nose, chin and cheeks is common at
ambient temperatures of 0C or above. At high
altitude, because of decreased air density, the wind
chill factor for a given temperature and wind velocity
is less than at sea level, but the wind velocity is
frequently very high.
As the skin temperature falls from -4.8C to
-7.8 C the risk of frostbite increases from 5 per cent
to 95 per cent. The risk of frostbite above an air
temperature of-10C irrespective of wind speed is
low, but below -25 C there is a pronounced risk
even at low wind speed (Danielsson 1996).

CONVECTION CURRENTS

Warm air rises and, if cooled, falls, setting up

convection currents. Around the neck this produces
a feeling of a draught as warm air from the skin rises
around the collar to be replaced by cold air. A closefitting collar reduces heat loss by this means.
AIR MOVEMENT
Air in the clothes is displaced by body movement,
which has a balloon effect on the trunk and a
pendulum effect in moving limbs. This effect is
reduced by close-fitting garments. However, in socalled windproof clothing, some wind penetration
and increased heat loss always occur. With increased
relative air movement as the outer layers of clothing
are cooled there is an increase in the thermal gradient
across the layers beneath.

23*5.2

Radiation

The transfer of heat by electromagnetic energy (i.e.

movement of photons from a warm surface to a
cooler one), can be a most important source of heat
loss and would still take place even if a vacuum
replaced the air. It is independent of air movement.
All objects warmer than absolute zero emit
radiation and therefore lose heat but they also gain
heat from objects around them by the same process.

Table 23.1 Wind speed and equivalent chill temperature

0
5
10
15
20
25
30
35
40

4
2
-1
-A
-7
-9
-12
-12
-12

-1
-A
-9
-12
-15
-18
-18
-21
-21

Little danger

Source: data redrawn from Mills (1973a).

10 mph = 16.1 km rr1.

-7
-9
-15
-21
-23
-26
-29
-29
-29

-12
-15
-23
-29
-32
-34
-34
-37
-37

-18
-21
-29
-34
-37
-43
-46
-46
-48

-23
-26
| -37
-^3
^6
-51
-54
-54
-57

Increasing danger
Flesh may freeze within 1 min

-29
-32
-34
-51
-54
-59
-62
-62
-65

-34
-37
-51
-57
-62
-68
-71
-73
-73

-40
-43
-57
-65
-71
-76
-79
-82
-82

Great danger
Flesh may freeze within 30 s

^6
^8
-62
-73
-79
-84
-87
-90
-90

Thermal exchange 275

Heat loss by radiation can be considerable in a

cold environment if the body is not covered and
insulated. Exposed face and hands lose heat to the
clear cold night sky by radiation, and gain heat from
the bright sun even in cold conditions. The greatest
source of heat gain by radiation is from the sun and,
in the clear polar or mountain regions where snow
forms a reflection, this effect is enhanced. An overcast sky diminishes radiation, and at night the Earth
loses heat by radiation to the black sky, with clear
nights being cooler than those when cloud acts as a
blanket and heat is retained.
The heat received by the body in full sunshine may
be two or three times greater than that generated by
normal metabolic processes. The amount adsorbed
on the surface of clothing will depend on posture, the
reflecting power of clothing surface, the absorption
of radiation by dust and moisture, and reflection
from the ground.
The amount of heat gained from solar radiation
will vary with the degree of cloud cover and type of
clothing. Black clothing adsorbs about 88 per cent of
solar radiation, khaki 57 per cent and white clothing
30 per cent.
In Antarctica, because of the clean air, solar
radiation reaches levels which at lower latitudes are
found only at high altitude. Heat gain from snow
reflection - the albedo - is an important factor at
high altitude and polar regions and may vary from
75-90 per cent in snow to 25 per cent if it is absent.
Heat gain also varies with the sun's 'altitude' in the
sky; it is low at dawn and increased at midday
(Chrenko and Pugh 1961).
In polar regions in summer, solar heat gain may be
two to four times greater than in desert, and at high
altitude the gain will be comparable. At extreme
altitude this may be crucial to survival, as diminished
oxygen uptake reduces heat output from exercise
with the result that body temperature may fall, and
heat from solar radiation keeps the climber in
thermal balance.

23.53

Conduction

Conduction involves a molecule-to-molecule transfer

of energy between two solids in physical contact.
Under most conditions heat exchange by this method
is small because the contact surface area between
individuals and the environment is small. However, it

may be of great importance during the rescue or

transporting of casualties; extra insulation must be
provided under the body when lying or sitting on a
cold surface. Localized frostbite may occur should the
body surface come into contact with materials of a
high thermal conductivity below zero temperature.
Touching the cold metal of an ice axe with bare hands
or spilling liquids onto the body can result in frostbite
or hypothermia. When clothing becomes soaked it
can lose up to 90 per cent of its insulating value.
Different tissues conduct heat at different rates.
Fat is a good insulator and skin over areas of fatty
tissue will cool more rapidly and to lower temperatures than areas where fat deposits are scanty. For
most tissues thermal conductivity is a function of
fluid content and tissue blood flow in a cold climate.
Prolonged vasoconstriction leads to fluid shifts and
increases central blood volume, which in turn leads
to a diuresis. A decrease in tissue conductivity results
but this is marginal considering the total insulation
required under cold conditions.

23.5.4

Evaporation

Unlike conduction, convection and radiation, where

heat may be both gained and lost, with evaporation
heat can only be lost.
During heavy exercise and in hot climates
evaporation of sweat is essential, and in a very hot
climate, where environmental temperatures exceed
skin temperature, the body may be actually gaining
heat by radiation, conduction and convection.
Evaporation therefore is the only method of heat loss
and means of preventing hyperthermia.
About 25 per cent of the total heat loss in humans
is by evaporation from the skin and respiratory tract.
Significant heat loss will occur by evaporation in the
process of drying clothes by body heat, particularly in
a wind or at altitude where the air is dry.
SKIN
As the epidermis is only slightly permeable to water,
the rate of loss by passive diffusion is small.
Insensible water loss and sweating account for
66 per cent of the evaporative heat loss under normal
conditions. Sweating occurs as a result of exercise
and emotion, particularly fear. During exercise
thermal balance is maintained by the heat of
increased metabolism being balanced by the heat loss

276 Thermal balance and its regulation

from the evaporation of sweat. However, if exercise is

stopped abruptly, heat continues to be lost from
evaporation of sweat on the skin and in clothing but
as the metabolic rate falls the individual cools.
Large amounts of fluid, over 1 L Ir1, maybe lost by
sweating, particularly with severe exercise or in a hot
environment. If the air is dry and there is a wind, heat
loss by evaporation is limited only by the rate of
sweat secretion. If the air is moist and still, loss is
limited by the rate of water evaporated from the skin.
In very cold conditions considerable loss may result
from the sweat generated through exercise first
evaporating, but then condensing and freezing inside
the outer layers of clothing. Increased sweating
therefore results in both heat and water loss.
RESPIRATORY TRACT

The temperature of expired air is below body

temperature and is probably not fully saturated with
water even at this lower temperature (Ferrus et al.
1984, Milledge 1992). Even so, with normal ventilation, heat loss amounts to about one-third of the
total loss from evaporation. At high altitude, with
higher ventilation rates, this will increase particularly
as the air is drier. In the cold, even at sea level, the
volume of body water lost through respiration is
large enough to cause dehydration and weight loss,
and may damage the upper respiratory tract.

23.6
REGULATION OF BODY
TEMPERATURE
In a cold environment normal maintenance of body
temperature is by balancing heat loss against heat
production, the main control being a central
'thermostatic' mechanism in the hypothalamus. This
regulates the body temperature within narrow limits
but it is not a simple on-off device. There is a
complex system of neurones linking input and
output with many cross-links, which produces a
graduated response.
Sensory input comes from central receptors along
the internal carotid artery, reticular part of the midbrain, the pre-optic region and the posterior hypothalamus. Peripheral receptors are situated in the
skin and stomach, and there is also clinical evidence
of receptors inside peripheral veins (Lloyd 1979).

23.6*1

Variation of body temperature

ORCADIAN RHYTHM
Adult rhythm develops after the age of 2 years. Body
temperature shows cyclic changes throughout the
day, with an early morning low (oral temperature
36.6 C) and a late afternoon high (37.4C). This
may be upset when prolonged daylight, as in polar
summer or darkness as in polar winter (Colquohoun
1984), disturbs the normal day/night ratio. Sleep and
mental depression lower the temperature settings
(Crawford 1979).
INDIVIDUAL VARIATION
Normally there is little temperature difference
between individuals but there are occasional
exceptions. A persistent core temperature of 35.536.0 C has been recorded.
LEVEL OF ACTIVITY

Activity leads to an increase in body temperature.

Heavy exercise will result in a high body temperature; sleep or quiet resting causes a fall in
temperature.

AGE
Shivering is not present in infants but develops as the
nervous system matures. Sweating occurs in children
and obesity retards heat loss. Over the age of 60 years
thermoregulatory capacity declines, less sweating
occurs and the vasoconstrictor response is reduced.
GENDER

The thermoregulatory response in women is similar

to that in men. However, the normal increase in
subcutaneous fat in women may make them less at
risk of cold injury under similar climatic conditions.
During a winter climb on Mont Blanc in France
Raymond Lambert, a well known Swiss climber who
reached 8530 m on Everest in 1952, suffered severe
frostbite with amputation of fingers and toes, but his
female companion Lulu Boulaz escaped unhurt.
During the menstrual cycle the core temperature is
0.5 C lower in the follicular than in the luteal phase,
probably due to increased progesterone levels.
During pregnancy the thermoregulatory system is
more sensitive to heat produced by exercise.

Heat loss 277

With the menopause both thermoregulation and

cardiovascular irregularities have been observed and
exercise at high environmental temperatures may be
particularly stressful.

23.7

HEAT PRODUCTION

Between 27 C and 29 C, the critical air temperature,

an unclothed person at rest can maintain the body
temperature, as basal metabolic heat is balanced by
heat loss.
Eating increases basal heat whereas malnutrition
decreases it and may result in hypothermia; exercise
increases heat production considerably.
23.7.1

Stock 1983). Although in humans, brown fat persists

into the sixth decade in the neck, mediastinum,
kidneys and suprarenal glands and around the aorta
(Heaton 1972), it constitutes only a very small
fraction of the total body fat.
The infant relies, for the most part, on NST to
maintain thermal balance, brown fat accounting for
25-35 per cent of its fat stores.
It is debatable how much norepinephrine can
increase heat production in tissues other than brown
fat. The breakdown and resynthesis of neutral fat are
a possibility, and protein catabolism is increased on
acute cold exposure (Goodenough et al. 1982).
The insulation of subcutaneous fat enables obese
people to withstand cold better than the lean, but a
lowered NST response has been found in post-obese
individuals (Jequier et al. 1974).

Shivering thermogenesis
23.7.3

Exposure to cold increases muscle tone and

metabolism and leads to shivering, which may
increase oxygen uptake up to fivefold. The onset of
shivering is controlled by central and peripheral
stimuli working independently (Lim 1960) and may
be triggered by external stimulus. It is progressive,
starting from the neck muscles, proceeding to the
pectoral and abdominal musculature and then the
extremities. Shivering metabolism is proportional to
lowered mean skin temperature when the core
temperature is constant and to the core temperature
when the skin temperature is constant (Hong and
Nadel 1979).
Although shivering is useful for increasing
metabolism in an emergency it makes coordinated
motor tasks difficult and energy resources are
depleted, hastening the onset of fatigue and
hypothermia. If cold exposure continues, considerable stored glycogen is burnt and the associated
water loss may be as high as 1.5 L. However, under
normal conditions this should be replenished in the
next 48-72 h.

23.7.2

Nonshivering thermogenesis

Nonshivering thermogenesis (NST), or lipolytic

thermogenesis, is the production of heat from
adipose tissue, especially brown fat. There is
controversy over the occurrence of NST in adult
humans (Hervey and Tobin 1983, Rothwell and

Activity

Maximal physical exercise (V02max) increases heat

production by 20 times the basal rate; about five
times the normal basal heat production can be maintained for several hours (Maugham 1984). In cold
conditions, additional heat may be produced
through shivering and, as this can occur during exercise, oxygen consumption will be increased.
Limitation will be imposed by altitude where
oxygen uptake falls and shivering may be inhibited.
In very cold conditions too, oxygen uptake may be
insufficient to meet the demand imposed by both
exercise and cold. Exhausted individuals and those
with malnutrition cannot increase metabolism
because of lack of substrate (Wang 1978) and will be
at increased risk from hypothermia.

23.8

HEAT LOSS

Overheating may, at times, be a problem in the

mountains, particularly on glaciers in still, sunny
weather. When body temperature rises due to
increased exercise or too much insulation, body heat
must be lost and vasodilatation occurs which raises
the skin temperature. Vasodilatation also increases
the transfer of heat from the core to the shell and the
amount of fluid available to the sweat glands.
Sweating is an important method of heat loss
which may be impaired by dehydration and drugs;

278 Thermal balance and its regulation

there are also individual differences in regional

sweating patterns (Hertzman 1957).

23.9

HEAT CONSERVATION

Heat conservation occurs by physiological methods

and by insulation of clothing and shelter.

23.9.1 Vasoconstriction
Below the critical ambient temperature of 27-29 C
cold receptors in the skin initiate subcutaneous
vasoconstriction which limits blood flow to the
peripheral shell and this results in a decrease in skin
temperature and reduced heat loss. The thermal
insulation of skin varies from 0.15 CLO on vasodilatation to 0.9 CLO on vasoconstriction (Burton
and Edholm 1955). (The definition of the CLO is
given in section 23.9.3.)
In the scalp there is minimal vasoconstriction and
this makes the scalp less liable to cold injury by
comparison with the limbs. At rest at -4 C, heat loss
from the head may be half the resting heat
production in a clothed subject (Froese and Burton
1957). However, the nose, face and ears do vasoconstrict and hence are liable to frostbite.

23.9.2

Countercurrent heat exchange

the limb. Thus the blood reaching the skin capillaries

is precooled and the temperature gradient between
capillaries and the skin surface is reduced; venous
blood is warmed and heat conserved.
The temperature gradient down the length of a
limb may be more important in the control of
insulation than the gradient from the deep tissues to
the skin (Bazett and McGlone 1927).

23.9.3

Insulation

The CLO, which was introduced in 1941, is a

practical unit of thermal insulation for describing
heat exchange in humans. One CLO will maintain a
resting, sitting subject, whose metabolic rate is
50 kcal nr2 Ir1 (209 k} nr2 Ir1), comfortable
indefinitely in an environment of 22 C with a
relative humidity less than 50 per cent and air movement 6 m min"1.
The CLO is not a rigorously scientific unit of heat
resistance but nevertheless is a useful working unit
for the comparison of insulation. It is equivalent to
the insulation afforded by ordinary business clothing
and underwear for a sedentary worker in comfortable indoor surroundings (Burton and Edholm
1955). The value for insulation of tissues is
0.15-0.9 CLO, for air 0.2-0.8 CLO and clothing
0-6.0 CLO. The importance of the insulating values
of clothes is obvious. Under certain extreme
conditions, tissue insulation may be important.

SUBCUTANEOUS GRADIENT
Subcutaneous temperature varies with the depth and
location of arteriolar and venous plexuses, being
highest at about 0. 8 mm from the skin. A drop in
temperature superficial to this is due to returning
venous blood being cooler than arterial blood and
heat from the arterioles being lost to the veins.
Fluctuations in temperature are controlled by
arteriolar-venous anastomoses; their opening results
in warm blood passing to the veins and the dissipation of heat.
LONGITUDINAL GRADIENT
Arterial blood loses heat in the surface capillaries and
returns to cool the body. Heat lost in this manner is
reduced as arteries and their accompanying veins
exchange heat through their walls along the length of

23.9.4

Tissue insulation

Heat transfer in the body occurs by mass flow along

the blood vessels, but, as the capillaries do not extend
to the superficial parts of the epidermis, heat is
transferred from the capillaries to the skin surface by
conduction. This rate of heat transfer is determined
by the number of capillaries and their caliber. The
thermal insulation of tissues varies from 0.15 CLO
on vasodilatation to 0.9 CLO on vasoconstriction;
countercurrent heat exchange prevents excessive
heat loss. Subcutaneous fat is the most important
form of natural insulation and, as fat has few blood
vessels, thermal conductivity is less than in muscle.
The greater the fat layer, the lower the skin temperature and the smaller the gradient between skin
surface and environment (Keatinge et al. 1986).

Heat conservation 279

Individuals with a good layer of subcutaneous fat will

still shiver, as the temperature receptors are in the
skin and thus superficial to the insulating layer.
However, the heat produced by shivering will be
retained by the subcutaneous fat and result in a
smaller fall in rectal (central) core temperature and
less increase in heat production. Obesity is, however,
rare in indigenous people in cold climates or at
altitude.
Sites where subcutaneous fat is thin or absent are
more liable to local cold injury. These include the
tips of the fingers, nose and ears.

23.9*5

Air insulation and wind chill

In the cold, air density increases and loss of heat by

radiation decreases, but this is almost completely
compensated for by an increase in heat loss by
convection. Heat loss varies with wind velocity and
the loss increases up to about 16 km tr1. At higher
speeds there is little further increase in heat loss.

23.9.6

Clothing

Insulation and protection from the wind are the

most important functions of clothing in dry conditions. In wet conditions waterproofing is an
important factor in maintaining insulation.
Insulation depends on trapped, still air and is
proportional to the volume of this air. To maintain
insulation, the trapped, still air must remain
immobile to prevent air currents and loss of heat by
convection. A windproof outer layer should prevent
a large proportion of wind penetration. Materials
should maintain their thickness after compression or
when wet, and the actual bulk of the material must be
low to prevent heat loss by condensation. To
maintain thermal balance it is as necessary to
facilitate heat loss as it is to maintain heat production
and preserve insulation (Adam and Goldsmith 1965,
Keighley and Steele 1981).
A variety of clothing is necessary in order to
change the amount of insulation to meet the
demands of heat production and ambient temperature. If only one material, such as fur, is used, this
causes difficulties; to vary insulation, clothing must
be available in layers which can be put on and taken
off as required to avoid overheating. Adequate and
easily adjustable ventilation improves clothing

adaptability and clothing should fit correctly without

pressure on underlying tissues.
As wetting may decrease insulation by up to
90 per cent, this should be prevented, but at the same
time allowing sweat to evaporate. If a completely
windproof and waterproof garment is used in freezing conditions, evaporated sweat will condense and
freeze on the inner surface and clothing will become
soaked, thereby reducing insulation. The outer layer
should therefore be permeable to water vapor, water
resistant to retard water entry and windproof to
prevent excessive air movement and diminish
insulation (Jackson 1975).
Clothing assemblies may now be so effective that
after many months in cold conditions there is a
possibility that an individual may become heat
adapted (Wilkins 1973).
The choice of materials varies, and wool and
cotton are popular. The crimped fibers of natural
wool retain 40 per cent of their insulating value when
wet, compared with 10 per cent for cotton. Natural
down provides excellent insulation when dry but not
when wet. Synthetic fibers are becoming increasingly
important. Some are hydrophobic (Stephens 1982)
and do not retain moisture. When used as a padded
jacket or trousers, these may not have such good
insulation when dry but insulate well when wet.
Clothing assemblies are very much an individual
matter, but recently several equipment innovations
have helped climbers at extreme altitude. Plastic
boots with insulating liners have reduced weight and
increased warmth and, when knee-length gaiters are
added, foot protection is excellent.
Underwear that absorbs sweat as well as giving
some warmth under a fiber pile garment seems a
thermally efficient combination, especially with an
outer layer of 'breathable' fabrics like Goretex. Over
the past few years a number of synthetic fibers have
been developed for insulation in jackets, trousers and
sleeping bags. Their qualities rival down and they
have the merit of not losing as much insulation when
wet.
TRUNK
Insulation of the trunk is relatively easy as little
movement takes place and bulky garments are more
acceptable than on the arms and legs. A nonirritant
garment should be worn next to the skin; this will
absorb sweat and skin debris. Whether this has

280 Thermal balance and its regulation

sleeves is an individual choice. Shirts or sweaters

usually form the next layer. A polo neck is often used
in continuously cold conditions as it diminishes loss
of heat around the neck by convection currents. If
more than one layer is worn, the size must be
graduated. Drawstrings around the waist or wrists
may prevent heat loss due to the bellows effect.
Padded jackets of natural down or artificial fibers,
with or without sleeves, are common and they
should extend over the buttocks to overlap the
trousers by a wide margin. Often these have a windproof outer layer. They should open down the front
and be easy to take off and put on.
LOWER TRUNK AND LEGS

The amount of movement at the hip and knee and

the close proximity of the skin of the inner thigh,
which can cause severe chafing if garments are badly
fitted, influence insulation. Long close-fitting underpants of soft weave wool or synthetic fiber are
commonly worn. They should fit well around the
ankles to prevent heat loss.
Padded trousers should not be so thick as to
prevent easy leg movements. Breeches or trousers
should be of hard-wearing material and the fly
opening should be easily operated. Gaiters are often
used, and prevent snow from entering the top of the
boot. Some boots have gaiters attached to the sole.
One-piece padded suits may be used in extremely
cold conditions; these should have convenient zips
for ventilation and excretion. Salopettes, which
extend up to the upper chest, are increasingly worn;
they provide a large overlap with the upper jacket
and are very warm.
FEET

Feet remain covered all day and are not inspected

as easily or as regularly as hands and, as a result,
frostbite and nonfreezing injury may remain
hidden for a long period. The design of footwear
for dry or cold conditions has improved markedly
with the development of a boot containing a
molded plastic outer shell, including the sole, and
an inner detachable boot of artificial fiber. As these
are separate, the outer shell is removed when in a
sleeping bag. The inner boot may be changed if it
gets damp. Friction occurs between the inner and
outer compartments when walking rather than
between the skin of the foot and boot. Because of

this blisters are less common, despite the rigidity of

the outer shell.
Leather boots are seldom used now in severe dry/
cold conditions but in World War II, the Russian
army issued leather boots several sizes too large
which could be stuffed with straw or paper, whereas
the German army had well fitting boots but suffered
more from cold injury of the feet.
The ideal boot has yet to be designed for wet/cold
conditions and most rely on the leather boot with or
without an insole, and regular changes of socks. Both
Thinsulate and Goretex have been incorporated in
boot design. Once the foot gets wet its temperature
falls quickly owing to small heat stores. Overboots or
gaiters improve insulation and should extend to the
knee. Crampon straps constrict the circulation of the
foot in leather boots, but clip-on crampons and plastic boots avoid this problem.
Socks must fit well and be kept dry; spare pairs
must be available in the rucksack. Feet should be
inspected regularly so that incipient cold injury,
blisters and infections are dealt with quickly.
Meticulous care of the feet by the British Army in
World War II resulted in a lower incidence of nonfreezing cold injury than in any other army in the
same theater of war.
HANDS

The multilayer principle is best, and a mitten with

four fingers in one compartment and a thumb is
warmer than a glove. Individual insulation of a finger
is less effective because the heat loss from the curved
surface of a small cylinder is greater than from a large
cylinder. As the diameter decreases to 6.5 mm, any
increase in the thickness of insulation makes little or
no difference to the total insulation.
Mittens or gloves should be windproof, water
resistant, permeable to water vapor and robust.
Dachstein mittens made of uncured wool are very
effective. As metals are good conductors, contact of
cold metal with a dry finger will cause a 'cold burn',
whereas a wet finger freezes to the metal and tissue
may be left attached. If it is necessary to use fingers
for fine work, contact gloves should be worn.
It is worth noting that few indigenous mountain
inhabitants wear gloves; this is partly due to local
cold acclimatization, but native garments do have
long fold-back sleeves that can extend beyond the
fingers.

Heat conservation 281

THE HEAD

The head is an important avenue of heat loss. The

most likely areas to freeze are the tip of the nose, and
ears and cheeks. The ears are easy to protect with
muffs or a hat, and a painful ear is a warning of
incipient cold injury. The nose and cheeks are less
easy to protect and face masks, though increasingly
used, tend not to be comfortable and therefore are
not popular.
A well designed anorak hood is essential for
protecting the face from the wind, driving ice and
snow particles. It must project well forward from the
face and have a stiff but malleable wire in its leading
edge. This enables the hood to be arranged so that it
protects the face from whichever angle the wind
comes; if necessary, only a minute hole need be left
through which the individual can see.
The use of a visor of tinted glass provides more
protection than individual goggles or dark glasses.
An oxygen mask may be incorporated into the visor.
METABOLIC COST OF CLOTHING

Working with multilayered Arctic clothing increases

the metabolic rate by 16 per cent by comparison with
carrying the weight of the clothing. This increase can
be attributed to the frictional resistance of one layer
sliding over the other layer during movement, and
the hobbling effect which interferes with movement.
WIND, MOVEMENT AND WETTING

If wind penetrates clothing, movement of the trapped,

still air can result in a 30 per cent fall in insulation. The

magnitude of this effect depends on the degree of wind

resistance of the clothes and the effectiveness of the
sealing at the neck, wrist and ankle. Movement also
can lower insulation to half its resting value. Exercise
in the cold may cause overheating and sweating; rain
may also wet clothing and as much as 50 per cent of
insulation may be lost by this means alone.
The combination of movement, wind and wetting
may cause a 90 per cent loss of insulation, as a result
of which the individual is essentially unprotected
from the environment.

23.9.7 Insulation and oxygen

consumption
From Table 23.2 it will be apparent that at 0C
ambient temperature, to maintain a core temperature of 37C with a total thermal insulation of
3.0 CLO it is only necessary to work at a rate
equivalent to an oxygen consumption of 0.5 L mirr1.
At sea level this is not difficult but, at 7000 m and
above, a steady rate of 0.5 L min"1 may represent
50 per cent of Vo2max. To remain in thermal balance
at an ambient temperature lower than 0 C necessitates either working harder or wearing more clothes.
If neither is possible, the individual will become
gradually hypothermic.
If insulation falls to 1 CLO, work rate has to
increase threefold to 1.5 L min"1 to maintain thermal
balance. If insulation falls even lower due to wetting,
a work rate in excess of 3.0 L min"1 is necessary. This
will not be possible for an exhausted or unfit individual who will become hypothermic.

Table 23.2 Calculated final body temperature (C) at an ambient temperature ofOC
for a 75-kg man dependent upon the total thermal insulation (clothes plus tissue) and
activity, measured as oxygen consumption

0.2
0.4
1.0
1.4
2.0
2.5
3.0
4.0
Source: from data of Pugh (1966).

0.5
2
4
12
23
24
32
38
52

1.0
4
9
24
34
48
58
-

1.5
6
14
36
50
72
-

2.0
8
18
48
66
-

2.5
10
23
60
-

3.0
12
28
72
-

282 Thermal balance and its regulation

23.9.8

Shelter

The main value of a tent is to provide protection

from the wind, though some modern double skinned
tents also have quite good insulating properties.
Igloos and snow caves provide good insulation by
virtue of the air trapped in the snow. This is
illustrated by an incident in 1902 on one of Scott's
early Antarctic expeditions. One member went
missing and a blizzard developed which lasted 48 h.
He took shelter and was covered by snow, falling
asleep for 36 h, after which he awoke and returned
unscathed (Brent 1974, p. 61.). Adequate ventilation
is important to prevent the accumulation of carbon
monoxide given off by stoves (Pugh 1959).

23.10
THERMAL BALANCE AT HIGH
ALTITUDE
Many factors common at high altitude contribute to
a negative thermal balance. Chronic fatigue, the
result of great exertion, loss of sleep and decreased
food intake are associated with loss of tissue
insulation and result in reduced metabolic heat
production (Young et al. 1998). Previous severe
physical exertion may result in increased heat loss
(from sweating) and decline in core temperature
(Castellanieffl/. 1999b).
Severe dehydration could impair maintenance of
body temperature (O'Brien et al. 1998) and if
shivering is inhibited for any reason the core temperature is likely to fall (Giesbrecht et al. 1997).
An altitude of 5800-6000 m seems to represent the
limit of permanent habitation (West 1986a);
although at this height exhaustion is not uncommon
after physical exertion, recovery with improvement
in work capacity does occur, though it takes longer
than at lower altitude.
Over 7000 m deterioration, both physical and
mental, is more marked, V02max falls, climbing rate
falls and frequent stops are necessary. In 1978
Messner (1979, pp. 178-92), in the first account of
climbing Everest without supplementary oxygen,
comments, 'We can no longer keep on our feet while
we rest . . . every 10-15 steps we collapse into the
snow and then crawl on again.' As a result negative
thermal balance is more common without supplementary oxygen because heat production is reduced

while heat loss, including respiratory loss from excessive hyperventilation, is considerable. As the V02max
near the summit of Everest is down to about
1.0 L min"1 (West et al. 1983c) the sustained oxygen
uptake cannot be more than about 0.6-0.7 L min"1
and heat production is diminished.
Heat gain from solar radiation, both direct and
indirect, plays an important part in maintaining
thermal balance. In sunshine the gain from this
source at 5800 m in snow is estimated at
1.463 MJ m-2 h-1 (350 kcal m-2 h-1) , compared with
0.522 MJ m-2 rr> (125 kcal nr2 Ir1) in desert
conditions at sea level (Pugh 1962b). Heat gain from
solar radiation at altitude is estimated to be
equivalent to a rise of about 20C in ambient
temperature. The difference between day and night
temperature at 6000 m may be 60-70 C, a considerable cold stress.
At extreme altitude, although clothing may be
adequate when moving, it may not be adequate to
maintain thermal balance at rest.
The climber without supplementary oxygen at
extreme altitude, despite being fully clothed, is never
far from hypothermia and frostbite (Ward 1987).
The use of supplementary oxygen at extreme altitude
combats cold and hypoxia. It restores warmth to cold
extremities and increases the chances of survival and
success by increasing the endurance and climbing
rate. Sudden failure of an open circuit oxygen set
causes shortness of breath, limb paresthesia and
incontinence of urine: in the closed circuit set,
collapse and partial unconsciousness have been
recorded.

23.11
FACTORS ALTERING
TEMPERATURE REGULATION

23.11.1

Introduction

Trauma, hemorrhage and nausea increase heat loss,

whereas exhaustion reduces heat production. Sleep,
anesthesia and alcohol also affect regulation of
temperature, and the extremes of age are associated
with increased risk of hypothermia. Abnormal
thermoregulatory patterns are found in some ethnic
groups living in cold environments. The core
temperature of sleeping aborigines drops further
than that of Europeans before causing discomfort,

Factors altering temperature regulation 283

and natives of Tierra del Fuego maintain a high

metabolic rate (Hammel 1964). Meditation by
Tibetan lamas may result in cutaneous vasodilatation
and possible increased metabolic rate (Benson et al.
1982).
Certain medical disorders and drugs predispose to
hypothermia.

will try to keep each other awake; there seems to be

sound physiological reasons for this as the lower
body temperature set point will allow body heat
content to fall before discomfort due to cold is
appreciated.

23*11*2

It is now recognized that alcohol may be an important contributory cause of death in cold environments. Its role is complex, but even quantities which
result in levels below those of legal drunkenness are
dangerous before working in the cold.
The inhibitory action of alcohol on cerebral
function can cause bravado and lessen the ability to
assess risk. Before exercise in the cold alcohol is associated with a decrease in blood glucose (Haight and
Keatinge 1973) which will increase the risk of
exhaustion leading to hypothermia and further
impairment of gluconeogenesis (Drinking and
drowning 1979). Cooling also decreases the elimination of alcohol (Krarup and Larsen 1972); as it is
also a sedative, there will be an increased tendency to
sleep with resulting failure to maintain body heat.
Freund et al. (1994) suggest that alcohol reduces
central core temperature during exposure to cold
and that the degree of reduction is related to the
blood alcohol concentration; also hypoglycemia
increases the reduction in body temperature caused
by the ingestion of alcohol.

Malnutrition

Malnutrition, by depleting the body stores, renders

the subject more liable to hypothermia. The
metabolic demands of cold are similar to, though less
marked than, those of exercise, and the combination
of cold, fasting, exercise and altitude will impose a
considerable strain on the body. As a result, mild
degrees of hypothermia are probably commoner
than realized at altitude (Guezennec and Pesquies
1985).

23,113 Sleep
The central thermostat is set at a lower level when the
individual goes to sleep, and the basal metabolic rate
is reduced (Shapiro et al. 1984). Heat production
when asleep is 9 per cent lower than when at rest and
awake. During rapid eye movement (REM) sleep the
skin temperature rises if the rectal temperature is
high and falls if the rectal temperature is low (Buguet
etal. 1979).
In non-REM sleep, oxygen consumption and
metabolic rate are at their lowest. During the night
there is a gradual reduction in heat production,
which rises just before wakening. The skin temperature drops during sleep, which may wake the individual because of a feeling of cold. Theoretically,
there is no danger from falling asleep in extreme cold
since each bout of shivering would wake the person;
however, an exhausted individual may not shiver and
thus will fall into a dangerous cooling sleep.
Mountaineers bivouacking in extreme conditions

23*11*4

23*11 *5

Alcohol

Regular exposure to cold

Normal responses to cold may be modified by

regular exposure. Divers regularly exposed to cold
may be susceptible to progressive and symptomless
hypothermia resulting in poor judgment and death
(Hayward and Keatinge 1979). During experimental
cooling it is possible, by slightly raising the skin
temperature at the start of shivering, to abolish both
shivering and the sensation of cold without arresting
the continued cooling (Keatinge et al. 1980).

24
Reaction to thermal extremes: cold and heat
24.1

284

Cold

SUMMARY
Cold is as important a factor as hypoxia in the stress
of high altitude. Humans react to cold more efficiently by behavioral means than by physiology and
the majority of the body's systems are involved. As a
result Inuits can live at environmental temperatures
of -70 C and similar temperatures are recorded by
mountaineers at great altitude.
Local cold tolerance but not general acclimatization occurs. Children, because of their greater surface area to weight ratio, are at greater risk of cold
injury than adults.
Because of the high solar load found on enclosed
glaciers and snowfields, minor forms of heat injury
can be a problem at high altitude. In addition snow
blindness and sunburn are common and may be
severe if adequate protection is not taken. Because of
temperature extremes at high altitude, it is possible
to suffer from frostbite and minor heat injury at the
same time.

24.1

24.1.1

COLD

Introduction

Humans reacts to cold more effectively by behavioral

rather than by physiological means. Clothing and
shelter enable Inuits to live in an environmental temperature of-70C. The opportunity to become cold
tolerant is limited in Europeans as, even at polar

24.2

Heat

290

bases, people may be out of doors for only

10-15 per cent of the time. Mountaineers, because
they live in unheated tents or snow caves, may spend
longer periods exposed to cold.
However, protective clothing is now so efficient
that the microclimate (environment beneath the
clothing) may be as warm as a temperate zone and
some degree of heat acclimatization occurs. Only
exposed parts, such as the hands, become cold
adapted and those used to working out of doors are
less liable than newcomers to frostbite. Local
acclimatization has an essentially vascular basis with
an increase in blood flow; improved tactile discrimination and less appreciation of pain occur in the cold
adapted (Hoffman and Wittmers 1990).
Most people respond to cold stress by cardiovascular and metabolic changes, but not all respond
equally. Some tend to raise their heat production by
shivering; others adjust more by peripheral vasoconstriction.
In subjects of different body size and composition
there is a wide variation in the amount of heat production resulting from shivering thermogenesis; thin
men shiver more intensely than fat ones. In small to
medium sized individuals, vasoconstriction with
light shivering precedes heavy shivering, whereas in
large men, because of their body size and subcutaneous fat, metabolic heat production is less
(Strong et al. 1985). Children, because of their
greater surface area to weight ratio, are at greater risk
of cooling than adults.
Acclimatization is a term that has been used in
relation to cold by many workers and certainly
changes, both short and long term, have been shown

Cold 285

after repeated exposure (Shephard 1985). However,

the term has been used in so many different ways that
it tends to confuse rather than clarify.

24*1*2

Metabolic response to cold

Hammel (1964) distinguishes three distinct patterns

of human response to moderate exposure of the
whole body:
those who increase their metabolic rate as body
temperature falls (urban dwellers)
those whose metabolic rate falls gradually as rectal
and skin temperatures fall below those of urban
controls (Australian aborigines)
those who start with a high metabolic rate which
declines slightly and is accompanied by a fall in
rectal temperature to a level no lower than that of
a white control (Alaculuf Indians).
Repeated exposure to cold results in a greater sympathetic response and improved cutaneous insulation (Young et al 1986). It appears that the type of
physiological response varies according to the
degree, length and frequency of exposure.
Figure 24.1 Cold tolerance in Bhutanese Highlander at 4800m.

24*1.3

Cold tolerance

Those who are used to working out of doors in the

cold can work longer than newcomers, are less liable
to frostbite and are less likely to need additional
clothing when the temperature drops (Butson
1949). Brown and Page (1952) noted that both the
skin temperature and blood flow in the hands of
Inuits were higher in cold temperature than in controls and when immersed in water the blood flow
did not decline so abruptly. It has been noted too
that when Tibetan highlanders are exposed to cold
they complain of less pain and shiver less than lowlanders. A similar phenomenon is seen in Australian
aboriginal bushmen who may sleep virtually naked
in the cold desert without shivering (Hammel
1964).
Pugh (1963) describes a remarkable degree of
cold tolerance in a Nepalese pilgrim who normally
lived at 1800 m. During the Silver Hut Expedition
1960-1 in the Everest region he spent 4 days at
4550-5300 m in midwinter, wearing only cotton

clothing and no shoes, socks or gloves. The temperature fell to -13 C at night and he slept in the open
with only a coat for covering but no protection from
the ground at a temperature of 0 C to -5 C. He
maintained a relatively high metabolic rate without
shivering but with further cooling exhibited only
light continuous shivering which did not interrupt
sleep, rather than the usual violent intermittent
shivering. The surface temperature of his hands
never fell below 10-12 C and his toes 8 C. He complained of neither pain nor numbness and as his
skin temperature did not drop below freezing he did
not suffer from frostbite. He did, however, develop
fissures in the skin of his feet, which failed to heal,
and became infected. It was for this reason that he
returned to lower levels. A similar ability to withstand cold has been observed in Tibetan practitioners of g tum-mo yoga, who are able to increase the
temperature of their fingers and toes by as much as
8.3 C (Benson et. 1982).

286 Reaction to thermal extremes: cold and heat

24.1.4

Skin and peripheral vessels

The initial response to cold on the skin is the contraction of the erector pili muscles with the development of 'gooseflesh'. Constriction of the cutaneous
vessels occurs and there is increased blood viscosity
with decreased blood flow.
On immersion of a finger in iced water, skin temperature falls to nearly 0 C and then rises. With continued immersion, the finger temperature fluctuates,
known as the 'hunting' phenomenon. This is due to
reflex (cold-induced) vasodilatation and increased
blood flow through arteriovenous anastomoses. The
temperature rise is greater in the distal than in the
proximal phalanges.
The explanation of 'hunting' appears to be that
cold paralyses the vasoconstrictor muscle fibers,
the vessels dilate, blood flow increases, the finger
warms, heat is lost and the cycle repeats itself. A
recent study at Kangchenjunga Base Camp on this
reflex (Van Ruiten and Daanan 1999) showed that
ascent to altitude (5100 m) blunted this response
(lower maximum skin temperature and lower
frequency of hunting) but with altitude acclimatization, the sea level response was partially
restored.
Pain is related to blood flow, being severe on vasoconstriction and improving on vasodilatation. With
increasing cold, tissue metabolism ceases, the skin
blanches and becomes waxy and pale due to continuous vasoconstriction. The bloodless region cools to
the environmental temperature and frostbite may
occur.
The general thermal state affects the peripheral
circulation, and local vasodilatation is greatly
increased when the individual is warm and reduced
when cold. The extent of peripheral vasodilatation
depends too on the area heated. Heating the face is
far more effective than the chest or leg in varying skin
temperature and blood flow to the hand.
Cooling of one part of the body surface results in
diminished blood flow to other regions also. When
the whole body surface is cooled there is a general
cutaneous vasoconstriction with diminished blood
flow to peripheral tissues (Burton and Edholm 1955,
pp. 140-1).
Both cold phlebitis and cold arteritis may occur on
prolonged exposure. Those with varicose veins
should consider treatment prior to long periods in
the cold.

24.1.5

Nerves

Exposure of the hands to cold, even above freezing,

impairs nerve function after a period of about
15 min, and this is not immediately reversed by
warming and may occasionally persist for more than
4-5 days (Marshall and Goldman 1976). There is
diminished skin sensation followed by a lessening of
manual dexterity. The critical air temperature for
tactile sensitivity is 8 C and for manual dexterity it is
12 C (Fox 1967). Above these temperatures performance is little affected, though the hands may feel
cold, but at lower temperatures performance falls
markedly. Not all tasks are equally affected and
impairment may persist after the hands have been
rewarmed to normal temperatures. Many climbers
returning from high altitude have some loss of sensation in their fingertips, which may last several weeks.
24.1.6

Muscle

Cold also decreases the power and direction of

muscle contraction and seems to have a direct effect
on the muscle fiber, as blood flow is not decreased
(Guttman and Gross 1956). Handgrip diminishes
considerably when the forearm is immersed in water
at 10C (Coppin etal. 1978).
Increasing failure of muscle function may be due
to a combination of failure of nerve conduction,
neuromuscular function and the direct action of cold
on muscle fibers. Cold muscles are notoriously liable
to rupture and the more explosive the activity the
greater the risk, hence the need for a warm-up before
taking exercise. Muscle is more vulnerable to cold
than skin or bone (Kayser et al. 1993).
24.1.7

Joints

The temperature of the joints falls faster than that of

muscles, and cold joints are stiff joints (Hunter et al.
1952). Cold increases the viscosity of synovial fluid
and, by reducing its lubricating qualities, it increases
the resistance of joints to movements, increasing the
risk of tearing tendons and muscles.
24.1.8

Cardiovascular system

A number of thermoregulatory systems designed to

reduce heat loss are brought into play immediately

Cold 287

on exposure to cold; these affect the cardiovascular

system with an increase in cardiac output, blood
pressure and pulse rate (Hayward et al, 1984).
Initially, catecholamine excretion increases but, as
core temperature falls from 31C to 29 C, this
decreases (Chernow etal 1983).
BLOOD PRESSURE

In normal people and untreated hypertensives, the

blood pressure is higher in the winter. This rise in
systemic blood pressure increases with age and in
thin people (Brennan et al. 1982). Exercise in the
cold usually decreases diastolic pressure but this may
be countered by the inhalation of cold air (Horvath
1981) and may precipitate angina because, with the
associated increase in ventricular pressure, the oxygen needs of the myocardium increase (Gorlin 1966).
On cold exposure, constriction of the peripheral
vessels shunts a large volume of blood into the capacitance vessels causing an increase in cardiac load.
With the same volume of blood restricted to a
smaller vascular bed a rise in blood pressure results
and angina or cardiac failure may be precipitated as a
result. A rise in systemic blood pressure is associated
with a risk of cerebral hemorrhage; the incidence of
stroke is increased in the UK in winter (Haberman et
al 1981).
INTRAVASCULAR CHANGES

Subjects exposed to cold for 6 h show an increase in

packed cell volume, circulating platelets and blood
viscosity. These increase the risk of thrombosis and
also the incidence of myocardial infarction, which
often occurs within 24 h of the onset of a cold spell,
as a house takes approximately this time to cool
(Keatinge et al. 1984). Mortality from ischemic heart
disease increases in direct proportion to a fall in environmental temperature and the rate rises after a few
cold days, especially in the elderly (Blows from the
winter wind 1980).
The factors of both cold stress and hypoxia should
therefore be taken into account in cases of vascular
disorders in young men at altitude (Ward 1975,
pp. 289-92) (Chapter 22).

24.1,9

Pulmonary artery

Acute exposure to cold is known to cause pulmonary

hypertension in sheep and cattle and this involves

peripheral sensory stimulation and the efferent

innervation of the pulmonary vessels (Bligh and
Chauca 1978, 1982, Will et al. 1978). At altitude this
may be added to the rise in pressure produced by
hypoxia, which is a local effect on these vessels.
However, Yanagidaira et al. (1994) found that rats
exposed to cold over a long period had no right ventricular hypertrophy.
In the Arctic many middle-aged and elderly Inuit
develop chronic obstructive lung disease which leads
to pulmonary hypertension and right heart failure,
or 'Eskimo lung'. These Inuit had been hunters and
trappers when young, which involved hard physical
work in very cold conditions. Similar respiratory
problems have been noted in white trappers and in
native and immigrant Russian workers exposed to
extreme conditions in Siberia. Inuit women and men
who did little or no winter hunting were relatively
free of pulmonary hypertension due to cold
(Schaefereta/. 1980).

24.1.10

Fluid balance

Exposure to cold causes peripheral vasoconstriction

with shunting of blood into the deep capacitance vessels. This results in an increased circulating volume
in a diminished vascular bed and an increased arterial pressure. The body responds to this excess volume
of fluid by a diuresis (Hervey 1973), initially caused
by the release of atrial natriuretic peptide (Atrial
natriuretic peptide 1986, Chapter 15.4). With further
body cooling, diuresis results from the failure of
tubular reabsorption of sodium and/or water and
occurs despite diminished renal blood flow and
glomerular filtration (Tansey 1973). The often severe
weight loss experienced by people exposed to cold
over a long period is due to fluid loss (Rogers 1971).
Complicating factors are numerous. Respiratory
fluid loss occurs during exercise in the cold and at
altitude (Hamlet 1983). Vigorous exercise in the cold
can also produce marked fluid loss due to sweating,
which the individual may not notice because the air
is dry and evaporation rapid. This loss may amount
to 1-2 L per day or between 0.74 per cent and
3.4 per cent of total body mass in 24 h (Budd 1984).
Cold also has a tendency to depress the sensation of
thirst, as does hypoxia and, as water may not be easily
available to mountaineers at altitude, dehydration is
common.

288 Reaction to thermal extremes: cold and heat

The severity of fluid shifts is directly related to the

time exposed to cold. Another complicating feature
is that the type of exercise associated with hill walking results in appreciable sodium retention and
expansion of the extracellular fluid at the expense of
the intracellular fluid. This may result in overt clinical edema of the face and ankles due to activation of
the renin-aldosterone system (Williams et al. 1979,
Milledge et al. 1982).
During rewarming the circulating blood volume
may increase to up to 130 per cent of its value prior
to cooling. This is probably due to a reversal of fluid
shifts, and the volume of fluid available for return
will depend on the duration of cooling. If rewarming
is too rapid, therefore, fluid overload may cause
either cerebral or pulmonary edema (Lloyd 1973).

24.1.11

Respiratory tract

It is generally believed that the mechanisms available

in the upper respiratory tract for warming cold
inspired air remove the possibility of cold injury to
the lungs. Certainly there has been no evidence of
damage to the lungs in those working at the South
Pole, in winter joggers or cross-country skiers
(Buskirk 1977). The inhalation of cold dry air can,
however, damage the epithelium of the upper respiratory tract in humans and dogs (Houk 1959) and at
7500 m on Everest Somervell, a surgeon, nearly suffocated from the sloughing of the mucosa of his
nasopharynx. He gives a graphic account:

the tracheal bifurcation. As the tracheal temperature

falls during hyperventilation, the mucosa shrinks and
becomes pale in the same way as skin does; this will
prevent the temperature of the upper airways from
rising and provide a thermal gradient for the recovery of heat and moisture during expiration.
Exercise may induce bronchospasm in patients
with asthma. Its severity is directly related to the rate
of respiratory heat loss and can be prevented by
inhaling warm humid air (Strauss et al. 1978).
However, asthmatic subjects seem to do well in general on high altitude expeditions, possibly because
the beneficial effects of removal from their usual
allergens more than outweigh any detrimental effects
of inhaling cold air.
Exercise in a cold environment can cause bronchoconstriction. During severe exercise in extremely cold
conditions horses may develop frosting of the lungs
and sled dogs show evidence of pulmonary edema
(Schaefer etal. 1980). There are also anecdotal reports
of Arctic hunters having 'freezing of the lung'.

24.1*12

Alimentary tract

Cold stress can significantly delay gastric emptying

and acid secretion. The initial reduction in both gastric secretion and pancreatic trypsin output is followed in the post-stress period by an increase. This
appears to be a nonspecific response, as normal postprandial function of the upper gastrointestinal tract
can be disturbed by other stressful stimuli
(Thompson et al. 1983).

When darkness was gathering I had one of my fits of

coughing and dislodged something in my throat
which stuck so that I could breathe neither in nor
out. I could not of course make a sign to Norton or
stop him for the rope was off now; so I sat in the
snow to die whilst he walked on ... I made one or
two attempts to breathe but nothing happened.
Finally, I pressed my chest with both hands gave
one last almighty push - and the obstruction came
up (Somervell 1936).

Because the environmental air is never fully saturated there is a net loss of heat and water when air is
exhaled and as much as 50-60 per cent of the heat
transferred to inhaled air may be lost on expiration.
If the individual is breathing quietly and at rest the
inspired air is equilibrated with body temperature and
has achieved full saturation by the time it has reached

24.1.13

Hormonal responses

ADRENOCORTICAL FUNCTION

In those with no prior exposure to cold, a rise in 17OHCS levels has been found. This may reflect the
nature and severity of the stress. There is disturbance
of sleep and shivering together with the painful sensation of cold. Cold-adapted individuals showed no
increase in 17-OHCS activity (Radomski and
Boutelier 1982).
ADRENOMEDULLARY FUNCTION

Norepinephrine secretion increases in the nonadapted

and remains raised (Weeke and Gundersen 1983),
whereas the well adapted showed no such increase.

Cold 289
Epinephrine secretion increased in both the nonadapted and adapted individuals (Radomski and
Boutelier 1982).
THYROID FUNCTION AND GROWTH
HORMONE
In rats and some other animals T3 secretion increases
in response to cold exposure but there is also evidence that the main stimulus to nonshivering
thermogenesis is a hypothalamic activity via the
sympathetic system (Galton 1978).
In humans, the possibility of an increased metabolic rate due to thyroid activity has been considered
but there is little evidence that it takes place in
response to cold exposure. Korean women divers
have a higher basal metabolic rate (BMR) in winter,
greater utilization of thyroxine (T4), increased thermal insulation and changes in peripheral blood flow
(Hong 1973). However, most studies designed to
show increased thyroid activity in response to cold
have failed to show any change that could not be
accounted for by increased physical activity (Galton
1978).
On acute exposure to cold there is inhibition of
growth hormone secretion (Weeke and Gundersen
1983).

24.1.14

Immune response

Hypothermia may compromise the immune

response with severe infection and little inflammatory response (Lewin et al. 1981). However, an acute
fall in the core temperature does not necessarily
affect the immune system (Brenner et al. 1999).
McCormack et al. (1998) consider that immunesuppression occurs in cold exposure with reverse T3
(rT3) being raised above normal values. The uptake
of rT3 on lymphocyte nuclear receptors increases and
this rise suggests a response to general physiological
stress.
Clinically, superficial wounds seem to heal more
rapidly when the patient is removed from the cold
and hypoxic environment of high altitude.

24.1.15

Fatigue and cold

Chronic fatigue combined with sleep loss, reduced

fluid intake and poor tissue insulation may result in

blunted metabolic heat production, and this can lead

to a fall in body temperature (Young et al. 1998).
Previous severe exercise may also lead to greater heat
loss and decrease in body temperature (Castellani et
al. 1999b). However, a short period of rest, sleep and
adequate food restores the normal response to cold
but thermal balance may be compromised until tissue insulation is back to normal, which can take several weeks (Westerterp-Plantagna et al. 1999).

24.1*16

Mental function

The decrease in cerebral blood flow associated with

hypothermia results from a drop in metabolism
(Hernandez 1983). There is an ideal level of temperature and humidity at which mental tasks may be
carried out, and an increase in cold stress decreases
the standard of performance, as well as decreasing
the rate of work (Enander 1984). Cold causes apathy
and distracts individuals from their tasks.
Performance in the cold depends on familiarity; well
motivated subjects can complete given tasks even if
the central core temperature has dropped (Baddeley
etal 1975).
Individuals exposed to both fatigue and cold stress
adjust their performance so that they maintain as
steady a core temperature as possible and limit their
heart rate to about 120 beats mhr-1. To maintain
maximum 'comfort' between various stresses, a
physiological compromise is reached, and, rather
than increase work output so that anaerobic exercise
is performed, a lowered core temperature is accepted
(Cabanac and LeBlanc 1983).
Accidents show an increase with low environmental temperature, possibly owing to loss of manual
dexterity (Goldsmith and Minard 1976). Workers in
cold stores have a reduction in the ability to concentrate, and personal irritability increases (Andrew
1963). Silly errors (verbal, mechanical and clerical)
may occur as a result of the inability to concentrate.
Subjects may not be aware of the drop in performance and consider that they had done particularly
well when, in fact, they had the greatest impairment
in function. The individual developing hypothermia
is not aware of any mental impairment, and may
totally lack insight (Hamilton 1980).
Exposure to cold produces mental stress and
changes in personality. Hallucinations are a sign of
incipient or actual hypothermia (Ogilvie 1977).

290 Reaction to thermal extremes: cold and heat

There are many accounts in the mountain literature

of people seeing and talking to a nonexistent presence, feeling abnormal fear or pleasure and hearing
footsteps or sounds when none exist. In the majority
of cases cold, hypoxia, fatigue, starvation or a combination have been present.
Hallucinations are said to occur when the core
temperature drops below 32 C, but they often occur
above this level (Hirvonen 1982). Although mountaineers at great altitude report hallucinations, similar findings have been recorded at sea level. Acute
hypoxia is not usually associated with hallucinations
(Hatcher 1965), which seem to occur when cerebral
hypoxia has been present for some time, suggesting
that this may be the result of the biochemical changes
resulting from hypoxia rather than the hypoxia per
se. Some individuals respond to hallucinations, for
example by paradoxical undressing, going berserk or
attempting to kill their companions (Wedin et al.
1979). Even on reaching safety, a hypothermic
hypoxic patient may be unable to identify exactly
where he has been.

24.2

24*2.1

HEAT

Heat injury

Heat injury occurs when heat production is greater

than heat loss and the combination of high temperature and high humidity blocks the mechanisms for
heat loss and predisposes to heat injury.
Basal metabolism alone can produce heat at
271-355 kJ h-1 (65-85 kcal h-1), enough to raise core
temperatures by 1C h-1, were it not for the various
mechanisms for heat removal. Moderate work done
can increase this fivefold, to 1254-2508 kJ h-1
(300-600 kcal h-1 and solar radiation may increase
heat gain by 627 kj h-1 (150 kcal h-1). Raised body
temperature, of itself, increases cell metabolism and
therefore heat production (Arrhenius's law).
As long as the air temperature is lower than body
temperature, 65 per cent of cooling occurs by radiation or the transfer of heat from the body to the environment.
Above an environmental temperature of about
37C, evaporation is the only method of heat loss
and, if humidity exceeds 75 per cent, heat loss by this
method falls and sweating exacerbates dehydration
without cooling.

Overheating can be a problem at altitude because

very high solar temperatures are common on
enclosed glaciers and snowfields such as the Western
Cwm of Everest. Climbing at night or before dawn
should be considered under these circumstances.
Temperatures inside a tent may be as high as 30 C
and a sun temperature of 59 C measured with a
black bulb radiation thermometer has been recorded
on Everest (Pugh 1955b).
PREDISPOSITION TO HEAT INJURY

Elderly people are less able to maintain cardiac output and dissipate heat and may be dehydrated. A previous myocardial infarct may also limit the ability for
vasodilatation. Obese individuals have more insulation and less relative surface area from which to lose
heat, hyperthyroidism increases heat production,
and large areas of skin affected by disease may interfere with heat loss by sweating. Various drugs may
predispose to heat illness, such as beta-blockers
inhibiting a compensatory increased cardiac output.
ACCLIMATIZATION TO HEAT

In contrast to cold, some general acclimatization to

heat does occur. It takes about 10 days to reach its
maximum benefit and requires up to 2 h a day of
daily exercise.
The mechanisms, though poorly understood, are
associated with increased aldosterone production
and sodium conservation. Sweating occurs at a lower
core temperature and may be more than double the
normal amount. An increased cardiac output results
in the increased delivery of heated blood from core to
periphery and, in addition, there is increased density
of mitochondria per unit of muscle which allows for
increased oxygen usage (Weiss 1991).
CLINICAL FEATURES OF HEAT INJURY

There are two main clinical stages: heat exhaustion,

of which 'glacier lassitude' is a part, and heat stroke.
Glacier lassitude has been well recorded since the
start of mountaineering over 150 years ago. It is
associated with extreme lethargy and dehydration, and loss of salt. It occurs when heat uptake
from solar radiation is considerable, and is
described particularly when climbing in a 'bowl of
snow'.

Heat 291

Heat exhaustion is a further stage, but the core

temperature remains normal. There may be 'flulike symptoms with faintness, anorexia, nausea,
vomiting and muscle cramps. Sweating is usually
present but diminished. The central nervous
system is usually normal.
Heat stroke is a true medical emergency. It is not
common among mountaineers but its possibility
should be recognized during an approach to the
mountain across hot desert. Sweating stops and
characteristically the core temperature is above
normal. Onset is rapid with the victim becoming
confused and uncoordinated; hypotension, tachycardia and tachypnea are common. All untreated
cases die with brain damage. The degree of residual cerebral damage in treated cases is directly
related to the time that has elapsed before treatment. A core temperature of 41 C or above has a
poor prognosis.

Rapid and prompt evacuation of heat stroke casualties to a hospital emergency department is mandatory. Rapid reduction in body temperature, control
of fits and adequate rehydration result in a
90 per cent survival rate (Hubbard et al. 1995).
COMPLICATIONS OF HEAT STROKE

Decreased renal perfusion can lead to tubular

necrosis and renal failure.
Muscle damage and rhabdomyolysis can produce
myoglobulinuria and exacerbate renal failure.
Hypoglycemia and hypocalcemia may occur.
Total body potassium usually decreases.
Liver enzymes may be raised.
Thermal damage to vessel endothelial cells can
occur with disorders of blood coagulation (Weiss
1991).

24.2.2

Injury from solar radiation

TREATMENT

For heat exhaustion, the patient must be taken out of

the sun and given fluids and salt.
For heat stroke, treatment must start immediately.
The body must be cooled as rapidly as possible.
Cooling must be promoted by any means, and fluid
(even urine) does not have to be cold to provide heat
loss by evaporation. Packs of snow or ice should be
placed on the body where the large blood vessels
come to the surface: at the neck, axilla or groin. The
limbs should be gently massaged to prevent peripheral stagnation and accelerate cooling. This technique avoids generalized vasoconstriction and
shivering. Cooling rates of 0.1 C min-1 have been
recorded. No fluids should be given by mouth and
patients should be taken to hospital as soon as possible and cooled rapidly.
In hospital the optimum treatment is controversial and includes peritoneal lavage, water spray
and fans, ice water baths and gastric lavage. One or
more methods may be used. Evaporation techniques to keep the skin at about 20 C, together
with ice packs to the axilla and groin, are practical
in that monitoring is easy to manage. Most patients
can be cooled to a core temperature of 38 C in less
than 40 min by this method. Cooling should be
stopped at 37 C to prevent overcompensation and
hypothermia. Intravenous fluids should be started if
necessary.

Light from the sun includes radiation of wavelengths

of 290-1850 nm; the proportion reaching the Earth's
surface varies with the season and atmospheric conditions. Much solar radiation is filtered out by smoke
or fog, but less by cloud. At high altitude these
screens are less effective and reflection from the
Earth's surface, especially where there is snow,
increases exposure.
SNOW BLINDNESS (PHOTOPHTHALMIA)

Snow blindness is an inflammation of the cornea and

conjunctiva due to ultraviolet light of wavelength
200-400 nm. At altitude this makes up 5-6 per cent
of solar radiation, compared with 1-2 per cent at sea
level. Snow reflects 85 per cent of light waves and the
eyes are particularly vulnerable.
Acute

Within a few hours the epithelial cells of the cornea

die. There is loss of surface adhesion and the cells are
brushed off the cornea by the mechanical act of
blinking. The corneal nerve endings are then
exposed. Within about 4 h, symptoms are felt that
range from a feeling of'grit in the eye' to excruciating
pain and sensitivity to light. The slightest eye movement causes spasm of the eyelids, pupillary vasoconstriction, eye pain and headache. There is
conjunctival inflammation, the eyelids are swollen

292 Reaction to thermal extremes: cold and heat

Chronic snow blindness occurs in those inhabitants

of mountainous and snowy regions over a long
period. Visual disturbances, with sensitivity to light
and chronic conjunctival inflammation, are
reported.

decreased in blacks, whereas blondes and redheads

are particularly susceptible.
Seasonal variation is striking. The intensity of
UVA doubles in the summer, whilst that of UVB
increases tenfold in the same period.
Certain drugs make the skin sensitive to the effects
of solar radiation. These include sulfonamides,
phenothiazines, dimethylchlortetracycline and thiazide diuretics. Visual reactions to sunlight can occur
in those suffering from lupus erythematosus, porphyria and albinism. In patients with abnormal sensitivity, prolonged use of antimalarial drugs such as
chloroquine may suppress or reduce this sensitivity.
Cold sores may be exacerbated by prolonged exposure to stray sunlight (Lomax et al. 1991).

Prevention

Acute

Inhabitants of mountainous regions have used primitive prevention methods for centuries. These
include yak wool and hair pulled forward over the
eyes, slits in wood, or cardboard strapped to the head
(see Figure 3.3, which shows yak hair gogles).
Glasses or goggles with lenses that cut out radiation of wavelength 250-400 nm are normally used
for protection. The quality of the lens is important,
and it can be made of plastic or glass. The main
advantage of plastic is that it is lightweight and
unbreakable, but it does not filter out all the ultraviolet light; glass is heavier, but niters out most of the
ultraviolet light. Ideally, the external surface is mirror finished to reflect light, and the internal surface
should not reflect light onto the cornea. The upper
and lower parts of the lens should be darker than the
central part, through which the wearer is able to see
clearly. Frames should have side and nasal shields for
protection against sun, and a safety cord must always
be firmly attached. A spare pair of glasses or goggles
should always be carried. Goggles should have adequate ventilation to stop them steaming up (Lomax
etal 1991,Petetin 1991).

Clinical features of acute sunburn, which vary from

slight erythema to considerable blistering, appear
within a few hours. The severity of the patient's condition varies with the surface area involved.
Treatment should include removal from the sun,
cold compresses, and corticosteroid cream.
Secondary infection should be treated with antibiotics. Following exposure to ultraviolet radiation
the rate of melanin formation increases and protects
the skin from further damage.

and the secretion of tears profuse. The condition lasts

6-8 h and disappears in 48 h.
Treatment includes cold compresses, hydrocortisone eye ointment, an eye patch to exclude light, and
the avoidance of light. The pupils should be dilated
with atropine and an ocular antibiotic used in case
corneal ulceration occurs. Analgesics may be necessary.
Chronic

SUNBURN

Overexposure to ultraviolet radiation of wavelengths 200-400 nm can damage the skin.

Ultraviolet B (UVB) (290-320 nm) is primarily
responsible for burning, tanning and the formation
of skin cancer. Ultraviolet A (UVA) (320-400 nm)
contributes to skin aging. Melanin is the ideal sunscreen, and burning, aging and skin cancer are

Chronic

Recurrent exposure over many years causes atrophy

of the skin and loss of elastic tissue with scattered
pigmented areas (liver spots). Most of the skin characteristics attributed to aging are due to exposure to
the sun, as skin on protected sites such as the buttocks appears 'young' enen in the elderly.

24.23

Skin cancer

Ultraviolet radiation causes skin cancer in mice, and

the epidemiological evidence for sunlight causing
skin cancer in humans is overwhelming. It is one of
the common cancers in the USA. The possible depletion of the ozone layer may cause a further increase
in skin cancer.
PREVENTION

Sunburn is preventable and exposure should be

graded so that skin can become pigmented. Clothes

Heat 293
protect better than sunscreens; dark, dry fabrics
are more effective than white, wet garments. The
under-surface of the nose and the chin, also the lips
and ears, are susceptible to reflected ultraviolet
light. Sunscreens containing molecules that absorb
ultraviolet radiation are now commonly used.
Dibenzoylmethanes absorb UVA and, in combina-

tion with screening agents against UVB, provide

effective sun protection over a broad range of wave
lengths.
It is important that children and young people get
into the habit of using sun screens as this will
decrease the incidence of sunburn, photo-aging and
skin cancer (Kaplan 1992).

25
Hypothermia
25.1
25.2
25.3
25.4
25.5
25.6
25.7

Introduction
Definition
Classification
Pathophysiology
Clinical features
Management
Methods of rewarming

294
295
295
296
298
299
301

SUMMARY
Hypothermia or general cold injury occurs when the
core temperature falls to below 35C.
Trekkers and mountaineers suffer from subacute
or exhaustion hypothermia which can happen in
both wet cold and dry cold conditions. In wet cold
when the environmental temperature is above zero,
the dangerous combination of wind and wetting can
decrease the effectiveness of insulating clothing to
such an extent that the core body temperature may
fall despite shivering and exercise. In dry cold when
the environmental temperature is lower, a similar
sequence of events can occur, particularly if an
impermeable outer shell is worn and insulating
clothing becomes soaked with sweat. Wind not only
lowers the temperature of exposed skin by direct
wind chill but also reduces the insulating properties
of clothing by blowing away entrapped warm air near
the skin.
Disorientation is an early feature of hypothermia
and may occur at a core temperature above 35 C. At
high altitude supplementary oxygen, adequate food
and fluid combat hypothermia, though many
climbers suffer from both hypoxia and incipient
general cold injury. Those who are not fit may be at

25.8
25.9

25.10
25.11
25.12
25.13

Associated therapy
Outcome
After drop
Ventricular fibrillation
Intravascular fluid volume
Complica'tions

303
303
304
304
304
305

risk, whether in wet or dry cold conditions, as they

cannot maintain thermal balance by sufficient
exercise.
Management in the field depends on preventing
exhaustion and maintaining body heat. In hospital,
treatment by either surface or airway rewarming can
be successful. Severe cases should be treated in a
cardiothoracic unit by central rewarming.
Death should never be assumed while the core
temperature is below normal, even though the
patient may appear dead. A number of cases have
recovered from very low core temperatures.

25.1

INTRODUCTION

Worldwide populations of 100 million or more may

be at risk due to cold injury, yet in civilian life the
condition is less common than in wartime. In all
campaigns carried out at an environmental temperature around freezing point cold injury is common
and environmental hazard is now a major factor with
armies in the field.
Early descriptions of cold injury do not distinguish
between hypothermia, freezing cold injury (frostbite) and nonfreezing cold injury (immersion

Classification 295

injury). However, a Tibetan medical text thought

to date back to 889 BCE mentions frostbite
(Parfionovitch et al. 1992).
Hippocrates wrote on the climate of different
lands and the influence of the climate on their
inhabitants, making many pertinent observations on
cold injury, including the occurrence of blisters,
blackening of the skin and tingling in the hands.
The number suffering from cold injury in badly
equipped armies was considerable. During the winter
of 400 BCE Xenophon led his Greek army of 10 000
through the deep snow in the mountains of Armenia
where they suffered greatly from cold. In 218 BCE
Hannibal crossed the European Alps and lost approximately 20 000 men in 14 days, mainly from cold. In
1812 Napoleon invaded Russia with 250 000 men and
returned 6 months later, his army decimated by
'General Winter' and Russian resistance, his dreams of
an eastern empire shattered. In the Crimean War
French troops had 5000 cases of cold injury in an army
of 300 000, and in World War I the numbers of
casualties due to cold in the British, French and Italian
forces were respectively 115 000, 80 000 and 30 000.
In World War II the Germans suffered 100 000
cold injuries requiring 15 000 amputations in
November-December 1942 alone (Vaughn 1942).
Of the 9000 US casualties in Korea 10 per cent were
due to cold (Orr and Fainer 1951) and in the
Falklands Campaign in 1982, 13.6 per cent of
casualties were due to nonfreezing cold injury
(Marsh 1983).
It has been suggested that the high survival rate
among exsanguinated casualties in the Falklands
War was partially due to the cold climate which
facilitates clot formation and lowered metabolic rate.
William Harvey knew about this, for at the Battle of
Sedgehill, 1642, when there was a frost, he remarked
that it 'staunched the bleeding'. He was familiar with
a good method of treating hypothermia: 'A pretty
young wench which he made use of for warmth's
sake' (Harbinson 1999).
In peacetime, cold injury occurs particularly after
natural disasters such as earthquakes during the
winter months. Polar travelers, mountaineers and
skiers are also at risk, despite improvements in
clothing, technique and equipment. Cavers, divers,
fishermen and swimmers are also exposed to cold
injury (Washburn 1962). Elderly and very young
people can be particularly liable, especially if their
nutrition is poor or if they are ill.

Accidental hypothermia is not confined to high

latitudes or altitude. In the Sahara where there are
peaks up to 3010 m the temperature may fall to
freezing at night (Pierre and Aulard 1985). Even in
Kampala, Uganda, where the temperature never falls
below 16 C cases have been recorded (Sadikali and
Owor 1974, Barber 1978). In the mild English climate
it is estimated that over 200 000 cases of hypothermia
occur each year. In Yekaterinburg, 1368 km east and
north of Moscow, where the mean winter temperature is -6.8 C, lower than anywhere else in Europe,
mortality increases when the mean daily temperature
falls below 0 C (Donaldson et al. 1998a,b).

25.2

DEFINITION

Hypothermia is defined as a lowering of central core

body temperature below 35 C. This is rather an
artificial definition as it takes no account of total
body heat and some people drop their normal
diurnal temperature as low as 35.5-36 C (RCP
1966).
Exposure is a nonmedical term used in relation to
cold to describe a serious chilling of the body surface
and is usually associated with exhaustion leading to a
progressive fall in body temperature with the risk of
death from hypothermia.
Cold stress is the term used to describe the
stimulus which starts the physiological thermoregulatory response to cold.

253

CLASSIFICATION

Hypothermia may be classified according to the

central core temperature:
mild: core temperature 35-32 C
severe: core temperature below 32 C.
It may also be classified according to length of
exposure:
acute: the cold stress is severe and overwhelms
normal heat production in minutes or hours
subacute: exhaustion is a critical factor together
with depletion of the body's food stores
chronic: a mild cold stress operates over perhaps
days or weeks.

296 Hypothermia

253*1

Acute hypothermia

Acute hypothermia is seen in victims of cold water

immersion. The cold stress of ice-cold water is such
that hypothermia supervenes rapidly despite normal
or increased heat production by shivering or exercise
at a time when food stores are still almost replete.
There is no exhaustion in these cases. Injured
climbers in cold environments may fall into this
category. There is little time for fluid shifts to occur,
and a victim who is rescued from cold water and
dried is likely to warm spontaneously.

253*2

Subacute hypothermia

Subacute hypothermia is the type usually seen in

mountaineers. The victim will have been out in
severe weather conditions for hours, perhaps
inadequately clothed and fed, suffering from
exhaustion, with low food stores. The cold stress is
not excessive and is combated by vasoconstriction
and increased heat production by exercise and
shivering. This maintains the body temperature
until exhaustion supervenes and core temperature
falls. Spontaneous rewarming is unlikely or slow
and every route by which heat is lost must be
blocked and additional heat added (see section
25.6). Fluid shifts between body compartments are
likely.

2533

Chronic hypothermia

Chronic hypothermia is associated with elderly

people living in inadequately heated houses,
especially if there is even a mild degree of hypothyroidism. There is mild, prolonged cold stress and
although the thermoregulatory response is not
overwhelmed it is insufficient to counteract the cold.
The temperature falls over days or weeks. There are
considerable fluid shifts between compartments
leading to cerebral and pulmonary edema and
occasionally death.

25*4

PATHOPHYSIOLOGY

Basal heat production generated by the body rises and

falls with body temperature. During exercise or

shivering when oxygen consumption may quadruple,

heat production can increase up to 15 times normal
and catecholamine secretion is increased to augment
heat production. Shivering muscles use free fatty
acids, and some are converted by the liver into low
density lipoprotein, which is important as a source of
heat production (Hartung et al. 1984). The main
sources of energy in endurance activities are free fatty
acids and lipoproteins and fitness depends on the
ability to use these.
Fat utilization appears to be increased by exercising in the cold (Timmons et al. 1985), and a high
body fat may retard cooling of the core during
exercise (Weller et al. 1997). At high altitude
enhanced fat metabolism spares muscle glycogen
(Costil etal. 1977, Sutton 1987).
The lower the level of fitness the lower the level at
which catecholamines are required to maintain
adequate heat production.
Heat production is linked to muscular work and
maximal oxygen uptake so that at altitude heat
production is inevitably diminished.
Increasing fitness increases Vo2max, efficiency of
oxygen uptake and cardiac output and combats cold
and altitude. In cold conditions oxygen uptake and
cardiac output need to be higher to maintain exercise
rates and this explains the occurrence of angina in
cold conditions (Lloyd 1996).
At sea level, even in very fit individuals, vigorous
exercise in severe cold may not provide adequate
heat and hypothermia can occur; in the unfit exhaustion and hypothermia occur sooner and more
rapidly.
Wind can also increase oxygen uptake by as much
as 60 per cent. In a gale, speed of walking is
diminished and skin cooling, which is almost entirely
dependent on the environmental temperature, is
increased. Obviously clothing insulation will modify
cooling but if protective clothing is soaked externally
by rain, or internally by sweat, loss of insulation
occurs.
In wet cold, the combination of wind, movement
and wetting can reduce clothing insulation to a
negligible figure and is the reason why hypothermia
occurs at temperatures above zero.
Older men too have a faster drop in core temperature when exercising in cold conditions (Falk et al.
1994). There are no data on older women.
At high altitude, V02max falls and with associated
dehydration and malnutrition heat production is

Pathophysiology 297

further diminished and hypothermia becomes more

likely. Climbers at great altitude on pre-World War
II expeditions often felt cold despite 'adequate'
clothing. However, this clothing was inadequate by
modern standards and, with their poor general
physical condition, incipient hypothermia and frostbite were common.
Alcohol decreases awareness of cold, increases
bravado and impairs both mental and physical ability
and thus increases the likelihood of hypothermia.
During cooling, vasoconstriction occurs which
reduces the volume of the active vascular bed; when
cold stress is removed the vascular bed is increased
and surface warming further increases this. With
peripheral vasoconstriction, fluid is transferred to
the deep capacitance vessels and this overload is
countered by a diuresis due to a decrease in the
antidiuretic hormone.
Depending on the diuresis of cold exposure, fluid
may shift from the intracellular to the extracellular
compartment and this will reverse on warming.

25*4.1

Exhaustion

A high work rate can maintain heat production and

body temperature in cold conditions. However, if
the work rate is too low, a fall in core temperature
occurs with increased shivering and sympathetic
activity, which is more marked in leaner subjects,
and would impair performance still further (Weller
etal. 1997).
With poor insulation, prolonged exercise in wet
cold conditions can lead to exhaustion, fall in core
temperature, diminution in shivering and resultant
hypothermia. In one case the individual cooled so
rapidly that he was unable to continue walking
(Thompson and Hayward 1996).
Dehydration for short periods may reduce the
vasoconstrictor response to cold but it does not cause
a decline in core temperature. Severe dehydration
may, however, impair fluid balance and therefore
maintenance of body temperature (O'Brien et al.
1998).
If shivering is inhibited for any reason, the fall in
core temperature is likely to be increased and
rewarming inhibited (Giesbrecht et al. 1997) but
neither shivering nor vasoconstrictor response to
cold is affected by the time of day (Castellani et al.
1999a).

Previous severe physical exercise may predispose

to greater heat loss and a greater decline in core
temperature when subsequently exposed to cold
conditions. Indeed, it has been suggested that further
exercise could in the short term increase the risk of
hypothermia (Castellani etal 1999b).
Chronic fatigue, the result of exertion combined
with loss of sleep, decreased food intake and reduced
tissue insulation are the types of conditions that
occur frequently on the battlefield and in the mountains especially at high altitude. They result in
blunted metabolic heat production which compromises the maintenance of body temperature (Young
et al. 1998). However, a short period of rest, sleep
and adequate food restores the thermogenic
response to cold; but thermal balance in cold conditions may remain compromised until tissue insulation is restored, which may take several weeks.
(Westerterp-Plantagna et al. 1999).
In some cases of death due to hypothermia, unfit
individuals have become exhausted and their
shivering inadequate to maintain core temperature
(Tikusis et al. 1999). Pugh (1967) has shown that the
oxygen uptake of a subject exercising at a given work
rate in wet cold conditions is 50 per cent higher than
it is in a dry cold environment. Continuing exercise
may, therefore, result in complete collapse, increased
heat loss and hypothermia, and shelter must be
found immediately.
A feature of hypothermia is amnesia, but a case of
amnesia has been recorded at a core temperature of
35.6C, that is, above the level set as the criterion for
hypothermia (35 C). This has implications for both
mountaineers and hill walkers (Castellani et al
1998).
Exhaustion may lead to a reduced cardiac stroke
volume, a falling peripheral resistance and shift in
the distribution of blood to the capacitance vessels
(Ekelund 1967). The failure of vasomotor regulation
with pooling of peripheral venous blood will cause
maximum heat loss in cold conditions. A low blood
pressure state has also been observed after ascent to
extreme altitude (Pugh and Ward 1956). The fall in
skin blood flow during exhaustion might render the
fingers and toes more susceptible to frostbite (Wiles
etal 1986).
During a demanding and strenuous climb, energy
intake may not equal work output (Guezennec and
Pesquies 1985), and depleting the body's glycogen
stores increases the likelihood of fatigue. If blood

298 Hypothermia

sugar is kept above fasting level, deterioration in

performance is prevented but an exhausted person
cannot increase heat production in response to cold,
and heat loss is inevitable with possible hypothermia
and death.

25.4.2

Death

Fluid overload occurs when the circulating fluid

volume exceeds the active vascular capacity, and
death may result from pulmonary and cerebral
edema and cardiac failure.
Continuous cooling may also cause death due to
ventricular fibrillation with the risk increasing as the
central core temperature falls. The commonest
trigger is mechanical irritation.
Hypoxia too may contribute to some deaths as
shivering can quadruple oxygen demand. Supplementary oxygen should therefore be considered for
all hypothermic patients.
Temperature is a poor guide to death, as recovery
has occurred from a core temperature of 9 C (Niazi
and Lewis 1958). Absence of cardiorespiratory
activity or a flat electrocardiogram is not an indication as the heart may still be working, but undetectably and 'as hard as stone'. However, cardiac
arrest due to cold does occur.

25.5

25.5.1

CLINICAL FEATURES

Mild hypothermia

Individuals suffering from mild hypothermia

complain of feeling cold and lose interest in any
activity except getting warmer. They also develop a
negative attitude towards the aims of the party and,
as cooling continues, become uncoordinated, unable
to keep up and then start to stumble. There may be
attacks of violent shivering.

25.5.2

Severe hypothermia

At core temperatures below 32 C there is altered

mental function and the patient becomes careless
about self-protection from the cold.
Thinking becomes slow, decision making difficult
and often wrong, and memory deteriorates. There

may be a strong desire for sleep and eventually the

will to survive collapses with the individual becoming progressively unresponsive and lapsing into
coma. Slurred speech and ataxia may be confused
with a stroke. Gastrointestinal mobility may slow or
cease, and gastric dilatation and ileus are common
(Paton 1983).
Individuals show a great range of response to cold
and loss of consciousness may occur with a core
temperature as high as 33 C or as low as 27 C,
depending on the rate of cooling. Consciousness is
usually lost at around 30 C but patients have been
reported to be conscious though confused at lower
temperatures than this (Lloyd 1972, Paton 1983).
Though shivering usually stops as the temperature
drops below 30 C, it has been observed at a core
temperature of 24 C (Alexander 1945). Some cases
have been reported to cool without shivering
(Marcus 1979) (Chapter 23).
When the temperature drops to below 30C,
ventricular fibrillation may supervene.
Survival depends on sufficient cardiac function to
maintain output adequate for brain and heart
perfusion. Cardiac function is more relevant to
survival than brain temperature.
The patient with profound hypothermia may be
indistinguishable from one who is dead. The skin is
ice cold to touch and the muscles and joints are stiff
and simulate rigor mortis. Respiration may be
difficult or impossible to register, the peripheral
pulses may be absent and blood pressure unmeasurable. In profound hypothermia pupils do not react to
light and other reflexes are absent.
The electrocardiogram (ECG) shows a slow
rhythm with multifocal extrasystoles, broad complexes and atrial flutter (Jessen and Hagelstein 1978).
There may also be J waves present (Osborne 1953).
Both hemoglobin and white cell count will be
raised because of a shift of fluid from plasma to the
interstitial space. Thrombocytopenia has been
reported (Vella et al. 1988).
Even when there is evidence of a total stoppage of
cardiorespiratory function, survival is possible
(Siebhke et al. 1975). A flat electroencephalogram
(EEC) is not a certain indicator of death in hypothermia. The only certain diagnostic factor is failure to
recover on rewarming (Golden 1973, Lilja 1983).
Before brain death can be diagnosed the core temperature must be normal (NHS 1974); however, brain
death maybe a cause of hypothermia (Table 25.1).

Management 299
Table 25.1 Clinical features of hypothermia

37.6
37
35
34
33-31

Normal rectal temperature

Normal oral temperature
Maximal shivering/delayed cerebration
Lowest temperature compatible with continuous exercise
Retrograde amnesia, clouded consciousness
Blood pressure difficult to measure
Progressive loss of consciousness
Muscular rigidity
Slow respiration and pulse
Ventricular fibrillation may develop if heart irritated
Appears dead
Voluntary movement lost
Deep tendon reflex and pupil reflex absent
Ventricular fibrillation may develop spontaneously
Pulmonary edema develops
Heart stops
Lowest temperature in accidental hypothermia patient with recovery (Maclntyre 1994)
Lowest temperature in cooled hypothermic patient with recovery
Rats and hamsters revived successfully

30-28

27

25
24-21
20
14
9
1-7

Source: adapted from Lloyd (1986a).

25.6

MANAGEMENT

The principles of management are to prevent further

heat loss, to restore body temperature to normal and
to maintain life while doing so.
Choice of technique will depend upon circumstances, facilities available and the experience and
skill of the doctor. In mildly hypothermic patients a
slow rewarming technique is acceptable, but for
severe hypothermia rapid, active rewarming should
be carried out. If there is no circulation the patient
should be transferred to a unit where rewarming by
heat exchange is possible. A summary of the technique is given in Table 25.2.

25.6.1

In the field

The management of hypothermia in the field is 'the art

of the possible'. Hamilton and Paton (1996) carried
out a survey and concluded that most rescue groups
attempting to measure temperature did so by the oral
method. A low-reading thermometer was carried by a
majority of teams. For reheating, commercial heating
pads were used by most groups. The incidence of
hypothermia was, surprisingly, the same for summer

and winter. Cardiorespiratory resuscitation in the field

was started in 76 per cent of cases and the criteria for
starting were the absence of a pulse, cardiac arrest and
the likelihood of rapid evacuation.
MILD HYPOTHERMIA
Individuals should be stopped from walking and
placed in shelter out of the wind, rain or snow. They
should be protected from further cooling and
warmed by any method available.
Ideally, wet clothing should be replaced by dry,
but if dry clothing is not available wet clothing
should be wrung out and put back on. If wet clothing, which has some insulating value, is left on, it
should be covered with an impermeable material to
prevent further heat loss. As large amounts of heat
may be lost from the head, it should be covered.
Warm fluids should be given, but never alcohol.
A patient with mild hypothermia can recover with
these simple procedures, but recovery will be
hastened if external heat is added (e.g. getting into a
sleeping bag with another person). Central rewarming methods have been described (Lloyd 1973, Foray
and Salon 1985) using warmed inhaled air which can
be applied in the field with suitable apparatus.

300 Hypothermia
Table 25.2 Summary of reforming technique
Mild hypothermia 35-32 C

Surface rewarming
Warm intravenous fluids
Warm inspired oxygen

Severe hypothermia 32Cand below

Warm intravenous fluids

Airway warming via endotracheal tube
Warm bath immersion
Peritoneal dialysis
Gastric lavage

If circulatory arrest occurs

Cardiopulmonary resuscitation
Airway rewarming
Peritoneal dialysis
Gastric lavage
Central rewarming via heat exchanger

SEVERE HYPOTHERMIA

The management of severe hypothermia in the field

will depend upon the local situation, possibilities for
evacuation and access to specialist medical facilities.
Where these are good, as in the mountains of Europe
and North America, patients should be evacuated as
soon as possible with the minimum of treatment in
the field. However, active treatment in the field has
been successful (Fischer et al. 1991). Aluminium foil
'blankets' and suits provide good thermal protection
in rescue situations (Ennemoser et al. 1988). When
bad weather delays evacuation the patient should be
rewarmed slowly and treated as gently as possible to
avoid ventricular fibrillation.
If cardiac arrest occurs in a hypothermic patient
this produces a dilemma for rescuers because it may
be due to some other cause because the heart may be
beating even if clinically undetectable. Mechanical
irritation of chest compression may trigger ventricular fibrillation with total loss of cardiac function.
However, a consensus seems to be:
If breathing is absent, becomes obstructed or
stops, then standard airway management should
be started including mouth-to-mouth
resuscitation.
Chest compression should be started if no
carotid pulse is detected for 60 s, if the pulse
disappears, or if cardiac arrest occurred within
the last 2 h.
Resuscitation should be started only if there is a
reasonable expectation that it can be continued
effectively with only brief interruption until the

patient can be brought to a hospital where full

advanced life support is available (Lloyd 1996).
Cardiac resuscitation has been continued for
6.5 h with ultimate success (Lexow 1991).
Misguided attempts at cardiac massage may
precipitate ventricular fibrillation (Mills 1983a).
The mortality rate from hypothermia in the field
is of the order of 50 per cent but with increasing
expertise in management this figure should
improve.
The diagnosis of death in hypothermia should be
made with caution because profound
hypothermia can simulate death. Strictly, the
diagnosis of death can only be made when the
patient fails to revive after the core temperature
has been brought to normal.

25*6.2 In hospital (Bohn 1987, Danzl et

al 1995, Lloyd 1996)
Those patients with mild hypothermia (32-35 C)
can be allowed to rewarm slowly on a general ward
and warm humidified oxygen can be given by mask.
Those with severe hypothermia (32C and below)
should be admitted to an intensive care unit.
Intubation and ventilation should be carried out
by a skilled anesthetist with adequate preoxygenation
to prevent cardiac arrhythmia, if there is:

absence of vital signs

coma
apnea
hypoxemia not corrected by oxygen by mask

Methods of rewarming 301

cardiac arrhythmia
aspiration pneumonia
hypercarbia.
If there is no pulse or respiration then full cardiorespiratory resuscitation should be carried out,
regardless of EGG activity. Between 30 C and 28 C
the heart may fibrillate spontaneously but the
presence of sinus rhythm does not mean that there is
a useful cardiac output, so immediate external
cardiac massage should be started.
Below 28 C the fibrillating heart will not convert
to sinus rhythm, so there is little point in using shock
therapy until the core temperature is above this
value. Cardiac pacing and atropine seem of little
benefit; dopamine can improve cardiac output. An
increase in filling pressure can be achieved by using
pneumatic trousers to decrease peripheral volume.

25.7

METHODS OF REWARMING

Even in hospital, with perfect insulation, the rate of

warming varies greatly at between 0.14C to 0.5 C
h-1, and failure to rewarm may occur. Too rapid
rewarming may result in fluid shifts with pulmonary
and cerebral edema. Young people, particularly those
in whom acute hypothermia was precipitated by drug
overdose, have a high survival rate when allowed to
warm spontaneously (Tolman and Cohen 1970). In
the elderly with chronic hypothermia, there is a high
mortality rate (Treating accidental hypothermia
1978) unless treatment is carried out in an intensive
care unit (Ledingham and Mone 1980).
In severe hypothermia, when the patient no longer
shivers, some method of active rewarming is necessary, as metabolic heat production is so low.

25*7*1

Peripheral (surface) rewarming

Peripheral rewarming may be carried out either

rapidly or at a slow to moderate rate; it is only
advisable for conscious patients suffering from acute
accidental hypothermia.
RAPID REWARMING
The conscious patient should be placed in a bath
which is then heated to 40-42 C, hand hot, as
rapidly as possible. The advantages are that it is the

fastest way of transferring heat, needs unsophisticated equipment, suppresses shivering and speeds
the feeling of well being. The main benefits occur
within the first 20 min of rewarming and the method
should only be used in the patient who is conscious,
shivering and uninjured and able to get into and out
of the bath with only minimal assistance (Handley et
al. 1993).
The disadvantages are that, by dilating the
peripheral circulation before the body temperature
has been fully restored, there is a danger of 'rewarming shock' (Golden 1983). Also, because of the
problem of maintaining the airway, this method of
treatment is not advocated in an unconscious patient
because cardiorespiratory resuscitation cannot be
used.
SLOW TO MODERATE REWARMING
This includes the use of hot water bottles, blankets,
hot water packs, temperature controlled cabinets and
cradles and hot water sarongs (Paton 1983). This
method requires an effective peripheral circulation
and most, but not all, patients do rewarm
(Ledingham and Mone 1980).
Superficial burns are an important hazard
associated with all forms of surface heating, and may
occur even when the temperature is quite low (e.g.
hand-warm hot water bottles) (De Pay 1982).
Another disadvantage is that, with peripheral vasodilatation, heat is further dissipated and cold blood
returns to the heart causing irregularities of rhythm
(Anderson et al 1970).
Surface hot water warming abolishes shivering
and oxygen demand is reduced. However, not all
methods of surface rewarming provide enough heat
and abolition of shivering may put the patient at
further risk.

25.7*2

Central rewarming

With central rewarming the heat is applied to the

central core of the body and warming proceeds outwards from within. The organs of the core, 8 per cent
of the body weight, contribute 56 per cent of the heat
production at rest in normothermic patients and a
higher proportion in hypothermia, as the muscles
and superficial tissues have cooled more than the
core. By concentrating the heat gain to the core,
thermal benefit will be significantly greater.

302 Hypothermia
AIRWAY REWARMING

The main thermal input conies from the body's own

metabolism and the main benefit is to stop heat and
moisture loss through breathing, rather than by the
additional heat supplied (Lloyd 1973). It is therefore
of value only when the rest of the body is adequately
insulated. This method is widely recommended in
hypothermia as it accelerates rewarming with
beneficial effects on cerebral and cardiorespiratory
function (Lloyd and Mitchell 1974). It accelerates
return to consciousness, restores respiratory drive,
stabilizes cardiac rhythm and improves output and
blood pressure. It abolishes shivering thus reducing
oxygen demand and reduces mortality in hypothermia secondary to exhaustion.
The aim is to produce warm moist air for the
patient to breathe without burning the face or larynx.
Various types of equipment are available:
condenser-humidifier, which traps heat and
moisture during expiration, returning both on
the next inspiration
electrically powered humidifier
closed circuit consisting of a soda-lime canister
and oxygen cylinder. The reaction between sodalime and expired carbon dioxide produces heat
and moisture (Lloyd 1986, pp. 199-203).
Portable equipment of this type has been used satisfactorily at 6000 m.
For first aid one can use a heat and moisture
exchanger with mask and tubing covered by clothing
and breathe the prewarmed boundary air close to the
skin. It weighs only a few grams and is easy to carry.
Airway warming has the advantage that it can
be used in the field and continued into the hospital.
It is noninvasive and can be combined with other
treatments.
VIA A HEAT EXCHANGER

In open heart surgery total body cooling and

rewarming is routine. From experience gained by
this method it was natural to suggest that similar
methods be used in severe hypothermia. This may be
considered the ideal method of rewarming since the
vital organs of the core are warmed first with
oxygenated warm blood and circulation is artificially
supported, though it is invasive. Blood is removed
from the femoral vein, warmed in a heat exchanger
and returned by the femoral artery. Heat may be

supplied very rapidly by this method and the body

temperature raised by 10 C in 1 h.
The heart is perfused directly with warm blood
and cardiac irritability is reduced. If hypovolemic
shock due to peripheral vasodilatation occurs, then a
warm heart can compensate better than a cold or
irritable one. A definite indication for extracorporeal
rewarming is ventricular fibrillation associated with
hypothermia (Braun 1985), and patients who are
'frozen solid and dead' with a core temperature as
low as 17.5 C have been resuscitated by this means.
The method is safe in experienced hands and is
becoming more popular in centers where open heart
surgery is routine or where cases of severe hypothermia are seen frequently.

25*73

Irrigation of body cavities

MEDIASTINAL

Thoracotomy and mediastinal irrigation have been

successful, but this is an open, invasive method
requiring a sophisticated team. It causes more
trauma to the patient, there is a risk of infection, and
it is doubtful if it is more effective than central warming by heat exchange (Paton 1983).
PERITONEAL

Peritoneal lavage is an efficient method of heat

transfer. The temperature gradients throughout the
body are more normal than with surface rewarming.
The inferior vena cava is warmed directly and thus
venous blood returning to the heart is selectively
warmed. Additional heat to the heart and lungs is
transferred via the diaphragm, and cardiac, liver and
renal functions are improved. It is a simple method
not requiring highly trained personnel and sophisticated equipment (Patton and Doolittle 1972,
Pickering et al 1977).
Problems include peritonitis, which is related to
perforation of the bowel, and respiratory insufficiency due to the pressure of fluid in the peritoneal
cavity. Recent abdominal surgery is a contraindication because of the possibility of adhesions.

25.7.4

Other methods

Intragastric balloons have been used, in which a

double lumen tube transports the warm fluid to and

Outcome 303

from the balloon. A double lumen esophageal tube

with a thermostat controlled pump has also been
tried (Kristensen et al. 1986). These offer some
promise as a method of warming the central core
without the sterile precautions needed for peritoneal
lavage. A technique using a modified Sengstaken
tube through which Ringer's lactate solution is circulated at 41C has been described (Ledingham 1983).
Enemas and gastric lavage have been described but
require larger amounts of fluid. Intracolonic
balloons may also be used.
Diathermy requires sophisticated and expensive
equipment, but it has considerable potential for
delivering significant amounts of heat by transmitting energy through the superficial tissues to the
deeper ones where it is converted to heat. Three main
types are considered by Harnett et al. (1983): ultrasonic, short-wave and microwave. There is a
considerable number of hazards and disadvantages
(Lehmann 1971).

25.8

25.8.1

ASSOCIATED THERAPY

Drugs

There is controversy over the use of corticosteroids

in hypothermia. Some recommend their use from
clinical experience and steroids have been given as a
last resort to apparently moribund mountaineers
with some success (Maclnnes 1971).

25.8.2

Electrolyte abnormalities

Electrolyte abnormalities may be found in hypothermic patients, but the pattern is completely
inconsistent. Hypokalemia should be treated by
giving potassium; calcium will protect against the
effects of hypokalemia on the myocardium.

25.8.3

Glucose

Hypoglycemia was an important factor in one series

of hypothermic patients (Fitzgerald and Jessop 1982),
but a high blood sugar may be found in cases of
hypothermia (nondiabetic) probably due to nonutilization of glucose by cold muscles; on rewarming,
the glucose level will fall. Hypoglycemia may precipi-

tate hypothermia and the center controlling heat

production may be impaired. In cases of exhaustion
hypothermia, glucose may be given to provide
metabolic substrate for rewarming (Maclnnes 1979).

25.8.4

Intravenous fluids

All intravenous fluids should be warmed to 35 C

during resuscitation in treating hypothermia. In
hospital a dedicated warmer is used, but in the field
heat packs or body heat can be used.

25.8.5

Oxygen

Hypothermia will have the effect of shifting the

oxygen dissociation curve to the left (i.e. increasing
the hemoglobin affinity for oxygen) (Chapter 9).
This means that there may be difficulty in giving up
oxygen in the tissues, which may then be hypoxic.
Therefore, there is a theoretical advantage in the use
of oxygen (which should be warmed) in cases of
hypothermia, though this has not been demonstrated. Bohn (1987) considers that all hypothermic
patients should be considered hypoxemic until
proved otherwise.

25.9

OUTCOME

All methods of rewarming have been used successfully but each has disadvantages and problems. Some
require equipment and expertise found only in
hospitals and, except for the simplest methods,
medical supervision is necessary. The majority of
methods are safe provided the patient is monitored
in intensive care. The method of choice depends on
the environment, availability of equipment and
experience of those who have to treat the patient. A
high serum potassium following prolonged cardiac
arrest may suggest an inability to recover (Bender et
al. 1995). Hypothermia compromises the host
defense mechanism with the possibility of bacterial
infection but with minimal inflammatory response
(Lewin et al. 1981). However, contrary to popular
belief that cold exposure can precipitate a virus
infection, the immune system is not affected by short
periods of cold exposure. The fall in core temperature resulting from cold leads to a consistent,

304 Hypothermia

significant mobilization of circulating immune cells,

and increase in natural killer cell activity and
elevation in interleukin-6 plasma levels (Brenner et
al. 1999).

25.10

AFTER DROP

The core temperature continues to fall before rising

after the individual has been removed from cold
water; this has been termed the 'after drop'. As many
deaths have occurred after removal from cold water
and because this collapse coincided with the time
that the rectal temperature was at its lowest (Golden
1983), it was assumed that death and the after drop
were connected and that ventricular fibrillation had
been precipitated by the continued cooling of the
heart.
However, Golden and Hervey (1981) have now
challenged the belief that the after drop is caused by
cold blood returning to the core from the cooled
peripheral circulation. In fact, if the rate of heat
production from core to periphery is high enough to
balance heat flow there is no after drop (Golden and
Hervey 1981). The way that heat flows through the
body tissues can explain the rectal temperature fall
(Webb 1986). Savard et al. (1985) have shown that
the after drop in core temperature precedes
peripheral vasodilatation in human volunteers
exposed to hypothermia. Moreover, at the time of
maximum peripheral vasodilatation, core temperatures had already started to rise. Slow passive
rewarming may therefore be used in mild hypothermia and rapid active rewarming is only indicated
for severe hypothermia. Inhibition of shivering may
increase the after drop and attenuate rewarming in
hypothermic patients (Hayward 1997).

25.11

VENTRICULAR FIBRILLATION

The exact mechanism involved in the production of

ventricular fibrillation due to cold has so far not been
defined. Changes in electrolyte concentration occur
but there is no general agreement on their interpretation. Hypoxia of the myocardium might be a cause
but, in hypothermia, oxygen carried in the blood is
adequate for the reduced myocardial work, though

sudden hypoxia may precipitate ventricular fibrillation in hypothermia.

Cardiac temperature may be very low without
ventricular fibrillation (Laufmann 1951) and the
direct effect of cold is often asystole. However, it
seems probable that the effect of cold blood on the
Purkinje fibers selectively cools them relative to the
cardiac muscle. This could result in ventricular
fibrillation following cardiac irritation (Lloyd and
Mitchell 1974).
Defibdilation below 28C is unlikely to be
successful, although there are some exceptions.
Ideally one should manage such patients in a cardiac
surgical unit. The circulation should be maintained
artificially until cardiac temperatures exceed 28 C
before attempting defibrillation, as too many
attempts are likely to burn the pericardium. However, with direct core rewarming, a heart in asystole
has started spontaneously at 24 C, and defibrillation
has been successful at 22.5 C. Bretylium tosylate is a
most effective antifibrillatory drug at low temperature and can be used prophylactically (Paton 1991).

25.12

INTRAVASCULAR FLUID VOLUME

The intravascular fluid volume is depleted in all

hypothermic patients, especially when hypothermia
is associated with septicemia and trauma. Incidents
of cardiovascular collapse and cardiac arrest during
rewarming may be due to vasodilatation in a
volume-depleted patient and not to after drop, the
toxic effects of metabolites or the effect of cold blood
on the heart.
Death may therefore be due to hypovolemia.
During cooling, there is a shift in body fluids from
the intravascular to the interstitial compartment,
causing overt edema, which is increased on rewarming. The severity of the shifts is directly related to the
duration of cold exposure.
During rewarming, reversal of fluid shifts occurs
most rapidly in the peripheral vascular bed, causing a
rise in central venous pressure.
Survival from hypothermia depends, therefore, on
a balance between the size of the vascular bed, controlled by vasomotor tone, and the circulating blood
volume, dependent on the extent of dehydration. It is
also dependent on the extent and rate of reversal of
the fluid shifts that occur during cooling. If vaso-

Complications 305
Table 25.3 Complications of profound hypothermia
Pneumonia and pulmonary edema
Gastric erosion or ulcer
Acute pancreatitis
Acute renal failure and hematuria
Temporary adrenal insufficiency
Hemolysisand disseminated intravascular coagulation
Myoglobinuria

central venous pressure monitoring; this should be

done routinely in hospital. If the blood pressure falls,
a rapid infusion of 500 ml of warmed fluid will, if
hypovolemia is present, raise the blood pressure
temporarily (Lloyd 1986, p. 74).

25.13

COMPLICATIONS

Source: adapted from Wilkerson et al. (1986).

motor tone is poor, death from hypovolemia may

occur, and fluid overload may cause heart failure;
dehydration may affect either.
The only sure method of distinguishing these is by

For the previously healthy hypothermic patient the

risk of serious complications is low. Many of those
listed in Table 25.3 result from pre-existing
conditions, chronic disease, malnutrition and
alcoholism (Wilkerson etal. 1986).

26
Frostbite and nonfreezingcold injury
26.1 Introduction
26.2 Frostbite
26.3 Nonfreezingcold injury

306
306
317

SUMMARY
Frostbite and nonfreezing cold injury are both forms
of local cold injury and may be associated with
hypothermia. Frostbite occurs when the tissues
freeze but its clinical features are related to both
freezing and thawing. Blisters may lead to superficial
or deep gangrene and prevention is by the use of adequate protective clothing and avoidance of windchill. Management is conservative with rapid
rewarming being most effective; infection must be
avoided and surgical intervention delayed. The
sequence of freeze-thaw-freeze, which is especially
detrimental, must be avoided. The sequelae of frostbite may last for many years.
Immersion or nonfreezing cold injury occurs at
tissue temperatures between 0 C and 15 C. It is commoner than is generally realized and nerve involvement is usual. It may progress to frostbite. Treatment is
by rewarming but sequelae are common. It is often
found associated with accidents and bivouacs when
maintaining body temperature is difficult.
Local cold stress may be associated with chilblains,
Raynaud's disease, Raynaud's phenomenon and
coronary artery spasm and other conditions.
26.1

INTRODUCTION

Many are cold, yet few are frozen - and frostbite

is not common. However, both nonfreezing

26.4 Avalanches, crevasses and bivouacs

26.5 Conditions associated with cold stress

318
320

injury (immersion injury, trench foot) and freezing cold injury (frostbite) may be present in the
same limb and both may be associated with
hypothermia.
Nonfreezing cold injury normally occurs at
0-15 C, though the upper limits are not precisely
known and feet exposed for some time in water at
26 C may become swollen, hyperemic and painful.
Freezing cold injury (frostbite) occurs at temperatures below 0 C in dry cold conditions, especially if
there is a wind or the tissues are wet. Frostbite may
occur in fully clothed individuals at extreme altitude
at subzero temperatures if oxygen uptake is insufficient for adequate heat production when the tissues
cool to the environmental temperature. Local cold
injury is not common in civilian situations, though
1500 cases were reported on 300 expeditions to the
Karakoram Mountains of central Asia (Hashmi et al.
1998).
In World War I about 115 000 British soldiers suffered from immersion injury and frostbite. In
2 months in World War II, 100 000 cases of local cold
injury occurred in the German army with about
15 000 amputations (Vaughn 1942).

26.2

FROSTBITE

Many clinical factors may precipitate local cold

injury. These are shown in Table 26. 1.

Frostbite 307
Table 26.1 Factors which may precipitate frostbite
Excessive reaction to cold, e.g. Raynaud's syndrome
Diabetes
Endarteritis- local (result of previous cold injury)
Endarteritisobliterans
Vascular damage due to trauma or infection
Arteriosclerosis
Thyroid hypofunction
Hyperhidrosis (congenital or acquired)
Hypovolemia (loss of blood or through shock)
Dehydration due to gastrointestinal disease or exercise
Nicotine
Metal spectacle frames or seats

26*2.1

Clinical features

DISTRIBUTION OF FROSTBITE
Any area may be affected but some are more prone to
cold injury because of pressure, position, lack of
insulating fat or liability to wetting. These include:
face: bridge of nose (due to spectacles), tip of
nose, chin (double chin especially), ear lobes,
cheeks, lips, tongue (due to drinking or sucking
snow or ice)
upper limb: fingers (particularly the index finger
in rifle shooting), head of radius, lower end of
ulna, olecranon, medial and lateral epicondyle of
humerus
lower limb: patella, head of fibula, subcutaneous
border of tibia, medial condyle of tibia, lower end
of fibula, lateral edge of foot, plantar aspect of toes,
dorsal surface of foot joints, soles of feet, heels
male genitalia: penis and testicles (difficulty in
fastening zip; wetting due to overflow incontinence); jogging in conditions of severe wind chill
(Hershkowitz 1977)
buttocks and perineum (sitting on metallic seats).
Cultural patterns may influence the site of frostbite. With long hair frostbite of the ears is unusual,
whereas short hair is associated with frozen ears.
Some activity at low temperatures associated with
inadequate foot gear (e.g. running shoes) may also
predispose to the development of cold injury; a similar type of shoe is used for cross-country skiing.
Drug abuse may also contribute to cold injury, as
nasal 'snorting' of cocaine causes vasoconstriction,
and this makes the nose more prone to cooling in a
cold environment.

26.2*2

Epidemiology

In the Finnish army, 1.8 per 1000 recruits suffer from

frostbite (Lehmuskallio et al. 1995). A retrospective
study of a 10-year period (1986-95) of personnel in
the British Antarctic Survey (BAS) showed that of 61
new consultations for cold injury in 43 individuals,
95 per cent were for superficial frostbite, 3 per cent
for hypothermia and 2 per cent for trench foot. The
incidence was 65.5 per 1000 individuals per year,
higher than that reported for soldiers stationed in
Alaska.
The prevalence of cold injury increases with a fall
in temperature in the BAS survey. It was not possible
to find any correlation between smoking and frostbite; however, prior cold injury was a significant risk
factor (Sumner et al. 1974, Cattermole 1999).
At the district hospital in Chamonix in the French
Alps, about 80 cases of frostbite are seen each year.
About 75 per cent are superficial; 57 per cent affect
the feet, 46 per cent the hands and 17 per cent the
face (Marsigny 1998).

26.23

Classification

First degree: superficial frostbite with redness and

swelling.
Second degree: blebs or vesicles occur in addition.
Third degree: deep frostbite; the tissue becomes
gray, dark blue or black.

Figure 26.1 (a) Superficial frostbite: gangrene (shaded area) is

limited to the superficial 2-3 mm of tissue, (b) Arterial thrombosis:
gangrene extends through all tissues.

308 Frostbite and nonfreezing cold injury

26.2*4

Clinical features

SUPERFICIAL FROSTBITE

In frostnip, the exposed skin (often of the tip of the

nose, cheeks or ears, which have been painful),
blanches and loses sensation, but remains pliable. On
rewarming, the part tingles, becomes hyperemic and
may have some skin desquamation several days later.
In superficial frostbite (Figure 26.la), skin and
subcutaneous tissues are affected; the skin becomes
white and frozen, with the deep underlying tissues
remaining fairly pliable. On rewarming the skin
becomes mottled and blue or purple and will swell.
Paresthesiae are common.

Within 24-48 h, blebs, initially filled with colorless

serum, appear. They are usually found where the skin
is lax, such as the backs of the hands or dorsum of the
feet (Figure 26.2). Later they may be filled with
serosanguineous fluid, which is absorbed, and a
black carapace forms (Figure 26.3). Often white
frostbitten tissue may become black without the formation of blisters.
The gangrene is superficial, not more than a few
millimeters thick (Figure 26.la), in contrast to that
seen commonly in hospital due to arterial thrombosis (Figure 26. Ib), where the gangrene involves all
tissue layers. This means that the surgical approach
must be more conservative in the case of frostbite
(section 26.2.9).

Figure 26.2 Blister formation, swelling and

gangrene on feet and ankles several days
after freezing cold injury.

Figure 26.3 Superficial frostbite showing

black carapace developing after collapse of
blisters on the toes.

Frostbite 309

The carapace is insensitive and fits like a lead glove

over the underlying tissue. If the contour of the
blackened tissue corresponds to the original part, tissue loss is unlikely, but if contour is lost, tissue loss is
almost certain. After some weeks, the blackened
carapace begins to separate at the line of demarcation, and a black, mummified cast of tissue peels off
like a glove or sock (Figures 26.4, 26.5). Hidden
pockets of infection or pus may lead to tissue loss in
both superficial and deep frostbite (Figure 26.6).
The underlying tissue is pink, unduly sensitive
'baby-skin' and there may be abnormal sweating. In
2-3 months it will take on a normal appearance.

DEEP FROSTBITE

Deep frostbite involves the deeper structures (muscle, bone and tendons), as well as the skin and
subcutaneous tissues (Figure 26.7). The part is insensitive, wooden and gray-purple or white marble in
color. Because tendons are less sensitive to cold and
the associated muscle groups are distant from the
injury, the part can be moved (Figure 26.8). Blisters
filled with dark-purple fluid may appear after some
weeks. Eventually dry gangrene and mummification
occur and a cast of the affected tissue separates.
Permanent loss of tissue is almost inevitable with

Figure 26.4 Frostbitten fingertips showing

blackened carapace and line of demarcation.

Figure 26.5 Same fingers as in Figure 26.4,

now showing separation of carapace from the
ring finger leaving a conical stump.

310 Frostbite and nonfreezing cold injury

come into play. The part swells and ischemia may

increase as a result of sludging, emboli and
thrombosis. Frostbite should therefore be considered as an injury both of freezing and of rewarming (Paton 1987).
SKIN

Figure 26.6 Deep frostbite showing loss of contour and

mummification with development of a pocket of pus.

deep frostbite. However, the limbs may return to

normal over a period of months, and amputation
should never be carried out precipitately. A deep
boring pain may be present throughout much of the
period.

26.2*5

Pathophysiology

Classically there are four stages of frostbite:

The pre-freezing stage occurs secondary to chilling and before ice crystal formation and is the
result of vasoconstriction. The tissue temperature
is 3-10C and cutaneous sensation is usually
abolished at 10C.
The freeze-thaw stage is caused by extracellular
ice crystal formation, with the tissue temperature
below 0C. The environmental temperature is
usually between -6C and -15 C. Because of
underlying heat radiation from deeper tissues,
skin must be supercooled before it freezes.
Susceptibility to freezing varies. Endothelium,
bone marrow and nerve tissue are more susceptible than muscle, bone and cartilage.
In the vascular stage, changes in the blood vessel,
plasma leakage, coagulation and shunting of
blood occur.
In the late ischemic stage, thrombosis, ischemia,
gangrene and autonomic dysfunction supervene
(McCauley et al. 1995). On thawing, capillary
patency is restored but blood flow declines
3-4 min later. Three almost simultaneous
phenomena occur on thawing: momentary vasoconstriction of arterioles and venules; restoration
of capillary blood flow; and showers of microemboli. On freezing, the cells remain in a 'metabolic
icebox' while frozen, but on rewarming, perfusion
restarts and a number of biochemical reactions

Skin freezes at -0.53 C but, provided the period is

short, this causes no lasting injury. After 11 min at
-1.9C it becomes red and tender for days, and
repeated exposures for 20 min or more at this level
cause blistering (Keatinge and Cannon 1960). To
freeze properly skin must be supercooled to -4 C, to
counter underlying radiant heat.
Cold injury is associated with hyperkeratosis of the
skin and atrophy of elastic fibers. The sebaceous
glands and hair follicles also show change; there is
atrophy of the root sheaths of hair and the nails
become brittle, thick and cracked.
BLOOD VESSELS
Considerable evidence points to the primary alteration in cold injury being changes in the vascular
endothelium. Seventy-two hours after freeze-thaw
injury there is loss of vascular endothelium in the
capillary walls accompanied by fibrin deposition the endothelium may be totally destroyed (Zacarian
1985)
Venules appear to be more sensitive to cold than
other vascular structures because of their low flow
rates. Arterioles with a flow rate twice that of venules
are less damaged by freezing; capillaries show the
fewest direct effects of cooling.
Normally, following intense vasoconstriction, the
skin temperature equilibrates with environmental
temperature, the stagnant plasma cools and viscosity
increases. On rewarming, vasodilatation occurs and
there is immediate recovery of microvascular

Figure 26.7 Deep frostbite showing profile of tissue loss (cf. Figure
26.1 b).

Frostbite 311

Figure 26.8 Deep frostbite of fingers with

mummification showing that movement is
possible because muscles are unaffected and
tendons are still intact.

perfusion, provided no thrombosis is present. If

pathological vasodilatation occurs with release of
histamine or other tissue metabolites, this results in
blood with a high hematocrit reaching the capillaries
and the velocity of the blood flow is decreased, red
cell aggregates appear and an increase in viscosity
occurs. This may trigger further retardation of blood
flow and further aggregation leading to complete
occlusion of microvessels with complete stasis and
gangrene.
Damage to blood vessels depends on the duration

of freezing with resulting plasma leakage and blister

formation. The blisters contain tissue breakdown
products associated with vasoconstriction, increased
leukocyte sticking and platelet aggregation. Analysis
of the blister fluid shows prostaglandins and high
levels of thromboxane to be present (Heggers et al.
1990). Due to the action of precapillary sphincters,
arteriovenous shunts open and close in cycles and
blood bypasses the frozen area. Complete closure of
the arteriovenous shunts renders the part avascular
and protects the body core from cooled blood and

312 Frostbite and nonfreezing cold injury

the patient from hypothermia (Greene 1943,

Washburn 1962, Schmid-Schonbein and Neumann
1985). Both phlebitis and arteritis may occur as a
result of frostbite.
ICE CRYSTAL FORMATION

If freezing is slow, interstitial ice crystals form which

enlarge at the expense of intracellular water, osmotic
pressure rises, and enzyme mechanisms are disturbed with resulting cell death. If freezing is rapid,
ice crystals form everywhere and rupture of cell
membranes is the result.

EDEMA

Primary edema: normally cold is associated with

tissue dehydration. However, the longer the limbs
take to cool the more likely edema is to occur,
possibly as the result of changes in tissue pH.
Secondary edema is the result of rewarming and
vasodilatation and forms within 12-25 h. Plasma
passes through the cold damaged capillaries into
the interstitial tissue. Associated exercise may
cause swelling of the feet, so-called exercise edema
(Williams et al. 1979).
BONES AND JOINTS

NERVES

Increasing cold and nerve malfunction are matched

by severe morphological changes to peripheral
nerves.
The main findings are an immediate increase in
the mean diameter of myelinated and nonmyelinated
fibers, marked edema, axon degeneration, and infrequent, segmented and paranodal demyelination.
There is selective vulnerability to cold, based on
nerve fiber diameter, with myelinated fibers being
more susceptible than nonmyelinated. Degeneration
of nerve fibers is probably due to increased permeability of endoneural vessels which leads to diffuse
edema, toxin production, changes in osomolarity
and increase in endoneural pressure. Although there
is clear evidence of ischemia in freezing cold injury
this is less clear in nonfreezing injury, though some
changes in vascular endothelium occur.
Once the temperature falls below freezing for
more than a few seconds degeneration occurs affecting all nerve fibers equally. There is complete necrosis of all structures within the perineurium, except
the endothelial lining of the blood vessels
(Peyronnard et al. 1977, Nukada et al 1981).
MUSCLE

In freezing cold injury to muscle, the degree of injury

depends on the amount of exposure. The superficial,
coldest layer shows coagulation necrosis, slow necrosis occurs in the intermediate zone and muscle
atrophy alone in the deepest layer; repair is by fibrous
tissue (Lewis and Moen 1952). Biopsy and ultrastructural analysis have shown vascular damage and
damage to membrane structure, contractile elements
and mitochondria (Kayser et al. 1993).

Bone cells are more sensitive to cold than overlying

skin. A clear line of demarcation occurs, but the
damage extends proximal to this. Epiphyseal cartilage is more sensitive than bone, and periosteal new
bone formation can occur. The direct action of cold,
or microvascular changes with end artery thrombosis, or both, may be the cause of the damage (Hunter
etal. 1952, McKendry 1981).
EYE DISORDERS

The eye and optic nerve are protected from cold by

the paranasal sinuses. Impairment of vision occurs
only in hypothermia and not with local cooling.
Conjunctivitis due to cold has been observed, along
with cold injury to the cornea, in downhill skiers and
ice skaters unprotected by goggles.

26*2.6

Factors concerned with frostbite

ENVIRONMENTAL FACTORS

The presence or absence of wind (wind chill) and

degree of temperature are important. As the skin
temperature falls from -4.8 C to -7.8 C the risk of
frostbite increases markedly. This risk is minor above
an air temperature of-10C irrespective of wind
speed, but below -25 C the risk of frostbite is pronounced even at low air speeds (Danielsson 1996).
The type of task, shelter available, duration of cold
exposure and whether the part is wet are also factors
(Molnareta/. 1973).
PERSONAL FACTORS

The type of clothing is important, as are intercurrent

disease, low morale fatigue, previous cold injury and

Frostbite 313

smoking. Previous vascular disease and use of vibrating tools will predispose to frostbite (Virokannas and
Anttonen 1993).

26.2.7

Frostbite and altitude

Though few statistics are available, frostbite at great

altitudes appears to be commoner for comparable
environmental temperatures than at lower altitudes.
Both cold and altitude raise the packed cell volume
and viscosity and slow the peripheral blood flow,
whilst cold injury to capillary walls leads to plasma
leakage and intravascular sludging. This local hemoconcentration will be increased at altitude and
impaired tissue nutrition and necrosis may occur
more rapidly. Dehydration, from whatever cause,
will also increase viscosity of the blood, and thrombosis may be encouraged due to relative inactivity.
Maximal oxygen uptake is progressively lowered
and, with it, the ability to increase heat production
through exercise and probably the ability to shiver
are decreased (Gautier et al. 1987). Hypoxia also
blunts mental function and precautions taken
against cold injury may be inadequate. Poor appetite
will lower calorie intake and loss of insulating subcutaneous fat will occur (Ward 1974).
The effect of altitude hypoxia on the tone of the
peripheral microvasculature is important in determining the risk of frostbite at altitude. However,
studies of this effect have given conflicting results
(Durand and Martineaud 1971, Durand and
Raynaud 1987).

26.2.8

Prevention

Different parts of the body may be subjected to

widely varying temperatures at any one time. For
example, the foot may be at below freezing in deep
powder snow with the environmental temperature
many degrees above freezing. Temperature variation
throughout the day is considerable and both feet and
hands should be kept as dry as possible. Footwear has
to perform many functions other than the prevention of cold injury, and there is no footwear available
at present that will prevent local cold injury under all
circumstances.
The most useful preventative measures are to limit
the period exposed to the possibility of cold injury,
keep warm, maintain hydration, and keep the part

dry and free from abrasion. In many situations, particularly wartime, these measures are not always
practicable.
The 'buddy' system is valuable for preventing
frostbite, especially in large groups. The party is
paired off and each member of a pair is responsible
for keeping a close rather than a casual watch on the
other. This is done at regular intervals to note early
signs and is the most effective form of early detection.

26.2.9 Treatment
Both superficial and deep frostbite may be associated
with hypothermia, which has priority in treatment. In
any event few patients present with simple frostbite
and the temperature gradient down the affected limbs
ensures that, if frostbite is present in the extremities,
some degree of nonfreezing cold injury will be present
proximally. In addition, many patients will have been
exposed to a freeze-thaw-freeze sequence with potentially disastrous results whatever the treatment; if there
is skin loss the tissues will have frozen solid. Associated
fractures may interfere with blood supply. At high altitude, dehydration, raised hematocrit, and exhaustion
with poor heat output will enhance cold injury.
The ten principles of management are:

'buddy' system (see above)

avoid further trauma
avoid freeze-thaw-freeze
avoid infection
keep clean
rewarm
maintain morale
delay surgery
treat associated conditions
avoid subsequent frostbite.

IN THE FIELD
Frostnip
The part should be warmed out of the wind by the
gloved hand or by placing the affected part in the arm
pit or under clothing. It should not be rubbed.
Within a few minutes sensation is restored and normal working can be resumed.
Frostbite
Under no circumstance should the part be beaten,
rubbed or overheated. Excessive heat from wood

314 Frostbite and nonfreezing cold injury

fires, heat from exhaust pipes of cars or from stoves

can give disastrous results and the part will become
burnt or baked because of cold anesthesia (Flora
1985). Rubbing with ice or snow does not rewarm
and causes tissue damage. Thawing in the field is
contraindicated, as this will immediately be followed
by freezing and the catastrophic freeze-thaw-freeze
sequence precipitated.
Before thawing, the frozen part should be protected to avoid trauma, but during mountain rescue
this may not be possible. Once thawing has started it
must continue and refreezing must be avoided. It is
better to walk on frozen feet to a low camp from
which evacuation is possible than to start warming
and have to be carried, or walk on partially rethawed
feet (Mills and Rau 1983).
IN HOSPITAL
Patients should be kept in pleasant surroundings and
given a high energy, high protein diet and antitetanus
serum. Broad spectrum antibiotics should be given if
there is any likelihood of infection; because of devitalized tissue this may take hold very rapidly, causing considerable tissue loss. The affected part should
be inspected daily. Morale must be maintained.
INVESTIGATIONS ,
Tissue viability should be assessed by clinical examination and Doppler ultrasound. Tissue and bone scintillography allows perfusion to be assessed more
accuratelythan with Doppler ultrasound (Salimi 1985,
Ikawa et al. 1986, Shih et al. 1988). Other research
methods include: thermal clearance and measures of
skin blood flow (Rousseleto/. 1982), xenon-133 muscle blood flow (Sumner etal. 1971, Nugent and Rogers
1980), muscle biopsy (Kayser eta/. 1993) andthermography. The temperature of the deeper tissues can be
measured by means of a special probe, thus distinguishing between superficial and deep frostbite
(Hamlet etal. 1977). Phosphorus-31 nuclear magnetic
resonance (NMR) scans can be used daily to follow
the state of the tissue with time (Kayser et al. 1993).
THAWING
Various methods of thawing have been used but, at
present, rapid rewarming is the most favored, as
greatest tissue preservation seems to occur and the
results in deep frostbite are reasonably good (Mills

and Whaley 1960, 1961, Mills 1983b, Foray and

Salon 1985). Gradual rewarming gives satisfactory
results with superficial frostbite but variable results
with deep frostbite. Rapid rewarming should be carried out in warm water, containing an antiseptic (e.g.
Phisohex) in a whirlpool bath or tub at 40-42 C for
15-30 min until thawing is complete. The temperature should be continuously monitored. Analgesics
are usually required and antitetanus prophylaxis and
antibiotics should be given.
Blisters should be left or fluid aspirated. After
thawing, the extremities should be elevated, and
enclosed in a 'burns' bag which has the advantage of
protecting from infection. Protection by cradles
avoids further trauma or pressure. Treatment in
whirlpool baths containing an antiseptic is continued twice daily; in this way necrotic and infected tissue is gently removed.
On discharge patients should be warned that they
will be more susceptible to frostbite.
MINOR SURGERY
Blebs are left intact if the contents are sterile or, if
infected, they are drained but the tissue left as a
cover. However, as the fluid contains tissue breakdown products which can cause continued
vasospasm, some advise repeated aspiration.
A thickened eschar, which may limit joint movement or even constrict normal tissue, can be split or
removed (Mills 1983b). Debridement or amputation
should be delayed for up to 90 days so that mummification is complete. Fasciotomy to release pressure
due to edema in tissue compartments has been advocated (Franz et al. 1978). Fractures should be
treated conservatively by closed rather than open
methods. Dislocations should be reduced immediately to prevent tissue pressure.
DEHYDRATION
The majority of patients are dehydrated, so rehydration with warmed fluids is important. Decreasing
blood viscosity with a plasma expander after blood
has been removed from the patient may be effective.
Dextran (or newer colloids) can also be given.
PAIN RELIEF
Pain in the lower limbs may be controlled with
epidural bupivacaine.

Frostbite 315

Sympathectomy reduces pain and decreases

edema. After this, the line of tissue demarcation is
said to appear more rapidly, and become more proximal. However, increased tissue preservation does
not necessarily occur and possibly the nonsympathectomized limb does better. Medical sympathectomy by means of intra-arterial reserpine and
intravenous blockade by the Bier technique has been
used with some success. Evidence in this area is still
anecdotal and there is need for good clinical trials.
NEW DRUGS

Iloprost, a stable metabolite of prostocyclin I2,

together with warming has also been used with some
success (Groechenig 1994).
Oxygen free radicals have also been postulated as
being important in the mechanism of frostbite tissue
damage. Pegorgotein is a product of conjugating a
long-acting version of the endogenous scavenger
enzyme superoxide dismutase with polyethylene glycol. It has been shown to make no difference to tissue
survival in rabbit frostbite injury (Muelleman et al.
1997). Aloe vera cream and oral ibuprofen have been
used for their local inhibitory effect on thromboxane
synthetase (Marsigny 1998).
PROTECTIVE FACE CREAMS

Cold-protective ointments on the face have traditionally been used by many in Finland during the
winter. Recently doubts have been cast on the effectiveness of these creams and a higher incidence of
frostbite has been associated with their use. An
experimental study using a skin model has confirmed that the thermal insulation was at best negligible and at worst reduced by creams (Lehmuskallio
1999, Lehmuskallio and Anttonen 1999).
OTHER THERAPIES

Hyperbaric oxygen appears to have been discarded

though it may be of value in the post-thaw period.
Unless infection is present, there is no indication
for antibiotics, but infection can take hold very
rapidly in devitalized tissue, causing considerable
tissue loss. The affected part should be inspected
daily for signs of infection and, if there is any
doubt, a broad spectrum antibiotic should be
started.
Thrombolytic enzymes have been evaluated (Flora

1985), but there is a risk, especially if intracranial

injuries are present.
Both anticoagulants and vasodilators have been
used but there is disagreement about their effectiveness. Tobacco should be prohibited. Biofeedback
training has been tried (Kappes and Mills 1984).
AMPUTATION

Premature surgery is a most potent cause of morbidity and surgical intervention should be minimal.
When amputation is necessary (Figure 26.9) closure
should, if possible, be by skin flaps rather than grafts,
and sufficient deep tissue should be removed to
achieve this. However, skin grafts have been successful. If infection is present a modified guillotine procedure is recommended with secondary closure.
Irrigation of the infected stump is often successful.
Necrosis of the stump is a hazard because of cold
endarteritis and trophic changes may also occur.
Active movements of the fingers after amputation
must be encouraged to avoid stiffness and the development of a claw hand. Isolated ulcers of the stump
may develop owing to deep-seated bone necrosis, or
osteomyelitis. Marsigny (2000) reports a case in
which amputation of both hands and both feet had
to be carried out to save the patient's life. Deaths
from frostbite have also been reported (Ward 1975,
p. 340).
Patients should be mentally prepared for treatment that can last months and involve many amputations and reconstructive surgery. They may need
much psychological support.
TRAUMA

The risk of frostbite in exposed subdermal tissue is

considerable. Devitalized flesh freezes in 1 min at
0 C if wind speeds rise above 2 m s-1. As exposed wet
tissues rapidly become frozen, tissue necrosis, wound
sepsis and delayed healing are common. Immediate
thermal protection by suture or a wound dressing is
necessary. The patient should then be evacuated.
Routine wound debridement should be carried out
and secondary suture performed as circumstances
dictate (Butson 1975).
If hypotension or hemorrhagic hypovolemia is
present the normal signs of hypothermia may be
masked. The risk of hypothermia is also increased
when partially perfused exposed tissue is at subzero
temperatures. When warmed, these hypothermic

316 Frostbite and nonfreezing cold injury

patients may start to bleed profusely from injured

tissues. The analgesic protection afforded by cold will
also be lost on rewarming (Pearn 1982).

26.2,10

Aftereffects

Both short-term and long-term sequelae of local cold

injury have been reported. Even at normal temperatures skin may crack, causing painful fissures and
ulceration. Fungating and ulcerating squamous cell
carcinomas of the heel have been reported 40 years
after frostbite. These were well differentiated, of low
malignancy and with no evidence of spread.
Treatment was by local excision and skin grafting.
Unstable scar tissue, chronic irritation and pressure
were factors in etiology (Rossis et al. 1982).
Fibrosis follows cold injury to muscle. There may
be persistent vasomotor paralysis, analgesia, and
paresthesia; both early anhidrosis and late hyperhidrosis have been reported. Axon regeneration in
both myelinated and nonmyelinated fibers, with full
return of nerve function, may take 9 months or
longer. A burning sensation in the feet has been
noted in 61 per cent after full recovery and
intractable pain may be present for up to 35 years
(Suri etal. 1978, Kumar 1982).
There may be persistent and marked vasospasm to
cold stimuli which continues long after the initial
stimulus has been removed. Re-exposure to cold is
likely to cause a relapse since a high incidence of
nonfreezing cold injury occurs in those with a history
of local cold injury.
Problems with rigidity of the feet, fallen arches and
osteoporosis are reported. New bone formation usually restores the normal radiographic appearance
(Francis and Golden 1985). Changes in the epiphyses
of children with frostbite can lead to cartilage and bone
abnormalities due either to the direct action of cold
on chondrocytes or to microvascular changes with
end-artery thrombosis, or both (McKendry 1981).
POLAR HANDS
Figure 26.9 Deep frostbite of forefeet (a) before and (b) after
disartkulation at the metatarsophalangeal joints; (c) the
disarticulated forefeet. (Reproduced with permission ofCJ.C
Renton.)

This is the name given to superficial and often very

painful fissures extending from the dorsal nail folds
distally. It affects those who work in cold conditions, in the polar regions, in mountains or in those
who have had frostbite. It may recur even after
healing when the hands again get cold. Treatment is
by closing the fissures with a human tissue adhesive,

Nonfreezing cold injury 317

N-butyl-2-cyanoacrylate,
(Ayton 1993).

a form

of superglue

Table 26.2 Clinical classification of nonfreezing cold

injury

RENAL FAILURE

Following severe frostbite of both lower limbs and in

nonfreezing cold injury of the feet in children,
rhabdomyolysis with incipient renal failure has been
recorded. Severe, long continued exercise may also
be a factor in muscle breakdown (Raifman et al.
1978, Ross and Attwood 1984).
PAIN AND NUMBNESS
Ten of 14 patients with pain and numbness in the
feet had a good response to continuous epidural
blockade with recurrence after blockade had ended.
Those with a limited response did well after lumbar
sympathectomy (Taylor 1999).

263

NONFREEZING COLD INJURY

Prolonged exposure of tissue to temperatures below

15 C, or to marginally higher temperatures in water,
will result in nonfreezing cold injury, often with lasting damage to muscles and nerves.
'Trench foot' is the commonest form of this condition and is a significant cause of injury in military
operations when, for combat reasons, long periods
have to be spent with feet in water or in deep snow.
Water both increases and accelerates the risk of
injury, as does any factor that impedes circulation to
the extremities, such as a cramped position, immobility, tight clothing, tight boots and tight socks.
Mountaineers are at risk when powder snow gets
into their boots by the ankle or is melted by foot
warmth; damp socks will increase cooling.
Exactly the same sequence occurs with the hands
in mittens or gloves made sodden by water or snow.
However, because the hands are easier to inspect and
keep dry and warm, 'trench hand' is uncommon.
Nonfreezing cold injury, though initially reversible,
becomes irreversible if cooling is prolonged. It often
occurs in tissues immediately proximal to frostbite.

263.1

Clinical features

It is convenient to classify the features into mild,

moderate and severe (Table 26.2).

Erythema
Edema
Temporary sensory
change

Edema
Hyperemia
Blisters
Persistent sensory
change

'Blood' blisters
Gangrene
Permanent
disability

When first seen, the affected part will be pale and

sensation and movement poor. The pulse may be
absent, but freezing has not occurred. If these features do not improve on warming, nonfreezing cold
injury is present.
After a few hours the part becomes swollen, numb,
blotchy pink-purple and heavy. After 24-36 h a vigorous hyperemia develops with a bounding pulse
and burning pain proximally but not distally. Edema
with 'blood blisters' appears and, if the skin is poorly
perfused, it will become gangrenous and slough. At
night a pain like an electric shock makes sleep difficult.
In severe cases there is a progressive reduction in
sensation. The joints become stiff and muscles cease
to function. To maintain balance the legs are kept
apart and the sensation of movement has been
likened to walking on cotton wool (Ungley et al.
1945). Repeated minor trauma, such as running,
associated with the neuropathy encountered in
nonfreezing cold injury, may result in severe blister
formation with partial thickness skin loss (Reichl
1987).
Hyperemia appears to be due to vasomotor paralysis with paleness on elevation and redness when the
part is dependent. This phase may last from days to
weeks, as may changes in sensation. Persistent anesthesia suggests neurone degeneration with the
prospect of long-term symptoms (Burr 1993).
A late feature is hyperhidrosis; this may lead to
blistering, maceration of the skin and infection. After
some months sensation and blood flow return to
normal but gangrene may also occur. Severe changes
occur more commonly and are more extensive in
dependent, immobile tissues, whilst poor nutrition,
fatigue, stress, injury and associated illness exacerbate the condition. Individuals who have had trench
foot have a significant risk of subsequent cold injury
in wet cold conditions (Ahle et al. 1990).

318 Frostbite and nonfreezing cold injury

263*2

Pathophysiology

Because water is such a good conductor of heat,

stored heat is lost rapidly and the deeper tissues,
nerves, muscles, blood vessels and bones may be
affected before there is any recognizable skin change.
Changes in nerve conduction and sensation are common, as are changes in vessel permeability, which
result in edema, blistering, and compression of
peripheral vessels (Francis and Golden 1985).
There is clear clinical and pathological evidence of
ischemia in frostbite, but this is less so in nonfreezing
cold injury, though some evidence suggests that a
cyclical reperfusion type of injury may occur (Irwin
etal 1994,1997).
Initially, there is vasoconstriction followed by
vasodilatation. Limb arteries exposed to nonfreezing
cold injury are not normally thrombosed, but this
may occur in injured limbs. Muscle damage may
occur due to direct cooling, as may fat necrosis and
atrophy (Friedman 1945). Infected wet gangrene
may result, but dry gangrene and mummification
can also occur.
After weeks or months, blood flow returns to normal but limbs may remain very sensitive to temperature changes, with cooling causing intense
vasoconstriction and warming intense vasodilatation. Profuse sweating, sensory loss and loss of muscle power may persist. Amputation may have to be
carried out.

2633

Prevention

Some degree of nonfreezing cold injury is much

commoner than normally recognized and the majority of those who spend long periods in cold conditions or at high altitude have some minor symptoms,
usually paresthesiae, that persist over a few months
and then disappear.
If the risk of nonfreezing cold injury is recognized then commonsense measures are normally
adequate to prevent its occurrence. The feet are
particularly at risk, as they remain covered throughout the day.
In World War I the British Army reduced the incidence of trench foot from 29 172 cases in 1915 to 443
cases in 1916-18 by rigorous and simple measures. In
1988 the incidence in one USA marine unit of 355
soldiers was 11 per cent. Tobacco smoking (but not

race) was associated with a higher incidence of

trench foot (Tek and Mackey 1993).
Preventive measures include:
Heavy socks should be worn in well fitting boots.
Clothes should be loose fitting, and the trunk kept
warm.
Boots and socks should be removed twice a day. Feet
should be washed, dried, massaged and warmed.
Those at risk should sleep with dry feet. Wet socks
and boots should be removed and dried.
Keep feet out of water, snow and mud when
bivouacking; elevate them if possible and keep
toes and feet moving.
Numbness and tingling are signs of trench foot;
warm the feet immediately.
Always carry a spare pair of socks (dry). They can
double as gloves.
Modern mountaineering boots with a plastic outer
shell and inner detachable boot of artificial fiber are
better for high altitudes than leather boots.

263.4

Treatment

The patient should be removed from the cold; whole

body warming should be started (Lahti 1982) and
dehydration corrected. Rapid warming of the part has
been advocated but not universally adopted. Because
of pain, analgesics should be given, the patient rested
and the part raised. Blisters that develop should be left
unless infected, when drainage should be carried out.
Sympathectomy does not appear to be very effective
as hyperemia occurs naturally.
Gangrene may occur later, and this may be more
widespread and affect deeper tissues more extensively
than freezing cold injury. Conservative management
should be adopted and surgical procedures kept to
the minimum. In the long term, nonfreezing cold
injury may be more serious than freezing cold injury
because of the unrecognized cooling effect on deeper
and more proximal structures.

26.4 AVALANCHES, CREVASSES AND

BIVOUACS
Frostbite and hypothermia many occur in victims of
avalanches, in those who fall into crevasses and those
who bivouac.

Avalanches, crevasses and bivouacs 319

26.4.1

Avalanches

About 80 per cent of avalanche victims survive if they

remain on the surface. In those buried to a mean
depth of 1.06 m, 30-40 per cent are alive after 1 h,
but only 10 per cent after 4 h. The victims should
therefore be located as quickly as possible (Dubas et
al. 199la). The main injuries caused by an avalanche
are asphyxia, hypothermia, frostbite and blast injury.
The main cause of death is asphyxia. This may be
due to inhalation of snow, rupture of the lungs, compression of the thorax, airway obstruction in an
unconscious patient, brain damage resulting in
depression of ventilation, or the air around the victim's face being used up. Gray (1987) records a
woman who survived after 20 min in a wet snow
avalanche where she was unable to breathe. He suggested that the 'diving reflex', which causes bradycardia, was triggered by the direct contact of the
snow with the face, and this, together with the relatively rapid onset of hypothermia, was an important
factor in survival.
Because there is variable permeability of air and
carbon dioxide according to the type of snow, a victim completely covered by snow must not be
assumed to have asphyxiated. It is because of this
permeability that dogs are able to scent buried victims. People have been known to survive for several
days if an air pocket is created.
The development of hypothermia is not
inevitable after being buried, because of the low heat
conductivity of snow and because the individual is
protected from the wind. If clothing insulation is
good and it remains dry the individual is likely to
remain normothermic (Dubas 1980). Removal from
the protection of avalanche snow will increase heat
loss in a wind and the rate of cooling may be as
much as 9C h-1. If the victim is unconscious,
mouth to mouth respiration or intubation and ventilation should be tried.

26.4.2

Crevasses

A fall into a crevasse can be fatal but, if not, the

weight of the victim's body can leave him wedged
with compression of the thorax. This is often associated with multiple injuries. The victim's body heat
will melt the ice and the climber will sink deeper and
deeper. The body will cool rapidly and many

instances are recorded where the victim has been

found dead from hypothermia.
The only way to unwedge the individual is to
remove the ice with a drill or ice axe, although a
thawing liquid can be very effective. A tripod leaning
over the crevasse is the best method of extraction. A
method of airway warming which can be carried out
while the victim is still trapped has been developed
(Foray and Cahen 1981, Dubas et al. 1991b).

26.4.3

Bivouacs and tents

Crevasses, snow caves and snow slots make good

bivouacs because of the low thermal conductivity of
snow. They should be out of the line of stone fall or
avalanche, and provide protection from wind, fatiguing wind noise and heat loss. In both Himalayan and
Alpine crevasses temperatures of 0 C at 3 m from the
surface have been recorded when the outside air temperature was well below this. A constant day and
night temperature of-7C was noted in a snow cave
at 5800 m when the outside temperature dropped to
-20 C at night; it was used for sleeping throughout
the Silver Hut Expedition in the Everest region in the
winter of 1960-1.
The temperature inside a tent is more liable to
considerable variation. At 6000 m in the Western
Cwm on the 1953 Everest Expedition, the temperature inside a tent dropped from 30 C to 0 C in 4 min
as the tent went into the shade at dusk and rose from
-5 C to 30 C in 2 h as the sun struck the tent at
dawn (Pugh 1955b).
When bivouacking on snow, individuals must
always protect themselves from the snow with which
their bodies are in contact. They should huddle
together and be enclosed as much as possible so that
exhaled warm air heats the body. The fetal position
exposes only 60 per cent of the body surface to cooling and therefore should be adopted. Occasional
movement will diminish the possibility of thrombosis. Crampons should always be removed, as metal
conducts heat away from the foot. If boots and socks
are tight they must also be removed; a rise of up to
8C in skin temperature has been observed on
removing a tight sock (Pugh 1950).
Attempts should be made to stay awake and not slip
into sleep with subsequent body cooling and
hypothermia. At extreme altitude, oxygen even at low
flow rates will counter exhaustion and cold injury.

320 Frostbite and nonfreezing cold injury

26.5
CONDITIONS ASSOCIATED WITH
COLD STRESS

26.5.1

Cold allergy

The clinical features of cold allergy, described by

Horton and Brown (1929) and Wanderer (1979), are
malaise, shivering, aching joints and generalized
urticaria. Susceptibility is transmitted as a genetic
dominant (Eady et al. 1978). Sensitized mast cells are
found in the skin; exposure to cold causes degranulation with release of mediators causing hypersensitivity both generally and locally. Wheals occur at the
sites of local cooling, and even inside the mouth on
taking cold drinks. Swimming may produce familial
cold urticaria. It has been suggested that cases of sudden death within a few minutes of entering the water
are due to undiagnosed cold urticaria (Cold hypersensitivity 1975, Ting 1984).

26.5.2

Chilblains

Chilblains are local inflammatory conditions developing as a result of exposure to cold and are more
frequent in humid conditions than in a cold dry climate, probably because humidity increases local
thermal conductivity. Women are more affected
than men, and inadequate clothing with subsequent
cooling is an important predisposing factor. Central
heating reduces the incidence of chilblains (Cold
hypersensitivity 1975, Lahti 1982).

26.5.3

Raynaud's disease

Raynaud's disease is a condition found most commonly in young women. On exposure to cold,
intense vasospasm occurs in the small arteries and
arterioles causing skin color to change from white
(ischemia) to blue (cyanosis) and then to red (hyperemia), usually with pain or paresthesia. This is
believed to be an exaggeration of the normal vasomotor response to cold. No organic lesion has been
found.

26.5.4

Raynaud's phenomenon

In Raynaud's phenomenon arteriolar narrowing

occurs secondary to a systemic disease such as

sclerodema or lupus erythematosus and patients may

suffer long-term sequelae including chronic nail and
skin changes and muscle atrophy. In some this condition may be due to cold agglutinin disease characterized by clotting and hemolysis in tissues exposed
to cold.

26.5.5

Asthma

Asthma may be exacerbated by breathing cold dry air

during winter activities such as skiing, trekking or
climbing, though in practice asthmatics generally do
well at high altitude (see section 27.3.1).

26.5.6 Coronary and cerebral

thrombosis
About 50 per cent of cold-related deaths are due to
coronary and cerebral thrombosis. Most deaths from
thrombosis appear to be due to a short outdoor
exposure rather than long exposure in poorly heated
rooms. Normal physiological responses to cold, an
increase in erythrocyte count, platelet count, blood
viscosity, plasma cholesterol and fibrinogen, platelet
aggregation and sympathetic tone, all contribute to
an increased risk of thrombosis. For a discussion of
the risk of altitude for coronary disease patients see
section 27.2.1.
Patients with underlying arterial disease are
thought to be prone to arterial spasm in response to
cold and therefore are at increased risk of death if
they exercise in the cold (Caplan 1999).
A case of acute myocardial infarct at 5900 m has
been recorded in a 29-year-old man. Within 6 h he
was helicoptered to Kathmandu where he recovered. Eight months later he had a normal electrocardiogram. This may have been a case of coronary
spasm associated with a raised hematocrit
(Hutchinson and Litch 1997).

26.5.7

Acrocyanosis

Acrocyanosis occurs almost exclusively in women

and is characterized by cold and blue extremities. It is
worse in cold weather but is also present in warm
weather. All peripheral pulses are present and the
symptoms are symmetrical and constant.

Conditions associated with cold stress 321

26.5.8

Livedo reticularis

Livedo reticularis is characterized by persistent

patchy red-blue mottling of the legs, and occasionally the arms, and is worse in cold weather. Chronic
ulceration may occur. It is due to intermittent and
random spasm of cutaneous arterioles with secondary dilatation of capillaries and vessels.

26.5.9 Cold hypersensitivity following

trauma and cold exposure
A number of conditions with a vasospastic component follow frostbite and trauma. Pain is a prominent feature, and the limb is pale and cold and may
show evidence of disuse atrophy.

27
Medical conditions at altitude
27.1
27.2
27.3
27.4
27. 5
27. 6

Introduction
Cardiovascular disorders
Lung disease
Blood disorders
Diabetes mellitus
Gastrointestinal disorders

322
323
325
325
326
326

SUMMARY
As increasing numbers of people go to high altitude
and at a greater age, medical advice on the advisability of these trips in those with existing medical conditions is more often being sought.
Clearly some illnesses make a trip to high altitude
foolhardy, but with many conditions which are well
under control it is possible to enjoy an adventure
holiday of at least modest proportions. However,
patients must understand their limitations and be
realistic in their expectations. It is also necessary to
plan ahead for eventualities, take any drugs that may
be required and understand their use and actions. It
is also important to be open and frank with the leader
of the trek or expedition and with one's companions
since any medical problem affects not only the
patient but also the whole party.
27,1

INTRODUCTION

With more and more people going to altitude for

adventure holidays, expeditions and skiing, doctors
are more frequently being asked to counsel patients
on the advisability of their trip. People are also continuing these pursuits into later life (including the
authors of this book) and thus are increasingly likely

27. 7
27.8
27.9
27.10
27.11

Orthopedic conditions
ENT conditions and dental problems
Obesity
Neurological problems
Mental outlook

327
327
327
328
328

to be suffering from chronic diseases which may

prompt questions about their fitness for altitude.
There are not many hard data on which to base one's
advice to such people but such as there is will be
reviewed in this chapter.
The effect of any condition that interferes with
oxygen transport will be increased by altitude, so
cardiac and respiratory conditions are particularly
likely to interfere with performance at altitude.
Apart from the effect of altitude itself, the mountain environment poses other hazards. The great
ranges are situated mostly in developing countries
and in wilderness areas where gastrointestinal problems are common and medical help uncertain.
Altitude holidays usually involve quite strenuous
exercise and put a strain on the joints, especially
knees, hips and backs. Finally, the different culture
and lifestyle of such a holiday impose psychological
stresses which may be too much for some people
unused to the difficulties and privations of such a trip.
There is also the consideration that on an expedition or trek the aphorism 'No man is an island'
applies with greater force than in normal urban life.
One member's illness affects the whole team and may
even imperil the safety of other members. Therefore
it is ethically imperative that if people know of some
pre-existing condition that might affect their performance, they should make it known, at least to the
leader or medical officer if there is one.

Cardiovascular disorders 323

As a general rule individuals should be as fit as

possible before they leave for a holiday at altitude,
though fitness is not protective for acute mountain
sickness (AMS).
Those who have problems with their health should
find out as much as possible about their condition
before setting out. The action of specific medicines
they use must be understood and an adequate supply
taken, particularly when regular doses are necessary
as with diabetes mellitus or asthma (Rennie and
Wilson 1982).

27.2
27*2.1

CARDIOVASCULAR DISORDERS
Coronary artery disease

has been symptom free for several months - there is

probably little risk in going to altitude (Halhuber et
al. 1985). The exercise of hill walking at low altitude
(470-1220 m) has been shown to be well tolerated in
patients with a history of myocardial infarction and
stable disease (Huonker et al. 1997). There was no
evidence of coronary insufficiency on continuous
electrocardiography (ECG) and echocardiography. A
patient (known to the author) with auricular fibrillation and good left ventricular function has been to
moderate altitudes (4000 m) with no problem.
Patients with poorly controlled heart failure due to
coronary artery disease should obviously be advised
not to go to high altitude. Those with well controlled
disease who can manage a high level of exercise such
as hill walking at low altitude may well be able to
cope with the added strain of altitude.
It must be remembered that cold tends to make
the platelets stickier and theoretically could increase
the possibility of infarction. Cold is also thought to
predispose to coronary artery spasm.

Coronary artery disease is one of the major causes of

death in men and women aged 40 or over. If angina of
effort is present at sea level it is likely that ascent to altitude will increase symptoms, especially in the first few
days before acclimatization has occurred. If exercise is
limited by pain and the exercise capacity reduced, it is
likely that symptoms will occur at altitude and the risk
of cardiac irregularities and infarction may be
increased. Clearly such patients should not consider
an active holiday at high altitude and even nonstrenuous trips for business or pleasure should be avoided.
Visits to moderate altitude by asymptomatic patients
with coronary artery disease are probably safe. Roach
et al. (1995) surveyed 97 older people visiting Vail,
Colorado (2500 m); 20 per cent had coronary artery
disease. They reported no adverse signs or symptoms.
Erdmann et al. (1998) studied a group of cardiac
patients with impaired left ventricular function but no
residual ischemia up to an altitude of 2500 m. They
were compared with a group of controls. In both groups
exercise capacity was reduced by altitude but there were
no complications or sign of ischemia. Elderly subjects,
even those with coronary artery disease, acclimatize
well at altitude (Levine et al. 1997), so elderly people
should not be debarred from going to altitude by their
age but it would be prudent for patients with such disease to limit their activities during the first few days at
altitude to allow time for acclimatization.

Patients who have had successful coronary bypass

surgery before any myocardial infarction and have a
good exercise tolerance can certainly enjoy an altitude
holiday. One such patient was the subject of correspondence in the Journal of the American Medical
Association and a subsequent editorial (Berner et al.
1988, Rennie 1989). He enjoyed a trek to 5760 m with
no adverse effect. Another was a 67-year-old climber
who enjoyed two Himalayan expeditions after his
operation, although on the second expedition his altitude ceiling was limited to 4700 m. Ambulatory monitoring of his ECG when climbing and asleep at
4700 m did not show any evidence of ischemia.
Patients can be warned that their condition may limit
their performance and accept that. However, their
fear, and that of their companions, centers on the risk
of sudden death due to cardiac causes. Clearly there
is a risk that the graft may block at any time but there
is no evidence that altitude may precipitate this event.
The same considerations apply to patients who have
had coronary angioplasty.

CARDIAC INFARCTION

RISK IN CARDIAC PATIENTS

A recent cardiac infarction is a contraindication to

ascent, but after a mild infarct - providing the patient

In the wider context of cardiac disease Halhuber et al.

(1985) found a negligible morbidity in 1273 'cardiac

CORONARY BYPASS SURGERY AND

ANGIOPLASTY

324 Medical conditions at altitude

patients' who ascended to 1500-3000 m. These

patients included 434 with coronary artery disease of
whom 141 had had myocardial infarction. Only one
of these had a new infarct at altitude.
A larger question is that of occult coronary artery
disease, especially in those with known risk factors
such as a family or smoking history, obesity, a sedentary lifestyle, etc. Risk factors that can be modified
obviously should be, although there will be little
benefit in the short term.
MEDICAL CHECK UP

Should doctors carry out 'check ups' and tests to identify any patients at risk? Is altitude a significant risk
factor for sudden cardiac death? Shlim and Houston
(1989) reviewed deaths amongst trekkers in Nepal. By
obtaining the number of trekking permits issued, they
were able to give a number for the denominator as
well. Out of 148 000 trekkers in 3.5 years there were
eight deaths, none of which was known to be cardiac
in origin although two were of unknown cause. There
were six helicopter rescues for cardiac reasons out of
a total of 111 evacuations. Two were men in their late
fifties with severe known cardiac disease; one was a
young man with persistent ectopic beats and three
had chest pain thought eventually to be noncardiac.
Thus the incidence of sudden death from heart attack
is low and if altitude is a risk factor for sudden cardiac
death the figures suggest it is a minor one.
So should a symptomless subject be advised to
have an exercise ECG test before undertaking an altitude trip? In view of the apparent low risk and the
known poor sensitivity of the test (50 per cent) the
answer should be no. Rennie (1989) argues that the
predictive value of such a test might be 0.
001 per cent, i. e. it would identify only one patient
with silent disease who would have a fatal event during a trip, for every 100 000 tests carried out! Further,
the specificity of the test being only 90 per cent, the
great majority of positive tests will be false positives.
So what should the general practitioner do when
asked for advice from someone proposing to go on
an adventure holiday to altitude?
Take a history including coronary disease risk factors, advise on these and encourage the patient to
get fit.
Check the weight and blood pressure; in the
absence of any evidence of disease, no further tests
are indicated.

Point out that 'getting away from it all' also

involves getting away from easy access to medical
treatment and that people going on such holidays
must take a greater responsibility for their own
health than they would on a standard package
holiday.

27.2.2

Systemic hypertension

Acute hypoxia has a variable effect on blood pressure

in hypertensive subjects but there is a tendency to
elevation both at rest and at exercise at 3460 m
(Savonitto et al. 1992). However, Halhuber et al.
(1985) found that mild hypertensives who ascended
and lived at up to 3000 m had few symptoms and
both systolic and diastolic pressures fell. No cases of
cerebrovascular accident or cardiac failure were
noted in 935 patients. This improvement was continued for 4-8 months after returning to lower levels.
Those with well controlled hypertension may go to
altitude. In two treated hypertensives, a 6-week stay
at altitudes of 3500-5000 m produced little change in
either systolic or diastolic pressure. Subjects with
borderline hypertension may well have higher pressures on going to altitude but at present there is no
evidence that this means greater risk of vascular incidents (though no evidence of risk does not mean evidence of no risk).

27.23

Other cardiac conditions

Patients who have had valve replacements should, in

general, not take hard physical exercise. Poor lung
function is more often associated with mitral than
aortic valve replacement. The risks of going to moderate altitude, provided anticoagulants are taken and
hard exercise avoided, are probably acceptable.
After repair of a ventricular septal defect, residual
pulmonary hypertension is not uncommon and
patients who have had a correction of Pallet's tetralogy may often have some residual strain on the right
ventricle due to obstruction of the pulmonary outflow tract. Ascent to altitude in both will increase
pulmonary artery pressure and may put the individual at risk of high altitude pulmonary edema
(HAPE).
Following operation for coarctation of the aorta
some residual cerebral hypertension may be present
and in theory cerebral edema may be more common.

Blood disorders 325

Providing cardiac pressures are normal, the ascent to

altitude following repair of patent ductus arteriosus
and atrial septal defect is probably acceptable.

older subjects, 9 per cent of whom had pulmonary

disease.

2733
273

273.1

LUNG DISEASE

Asthma

Asthma is very common and sufferers are often

young and active so the question of the advisability of
an asthmatic individual undertaking an altitude trip
is a common one. An attack of asthma may be provoked by cold air and exercise but in fact many asthmatic patients have less trouble at altitude than at
home, possibly because the freedom from inhaled
allergens is of greater importance than the effect of
hyperventilation in cold air. This impression is born
out by a recent study by an Italian team working at
the Pyramid laboratory at Lobuje (5050 m) in Nepal.
They found that bronchial responsiveness in a group
of asthmatics was reduced at altitude compared with
sea level (Allegra et al. 1995). Also the increased sympathetic and adrenocortical activity will counter the
bronchoconstriction of asthma in the first few days at
altitude. The importance of taking a sufficient supply
of medication and using it regularly must be stressed.
There is no evidence that asthmatics are at greater
risk of AMS than nonasthmatics, though it must be
presumed that poorly controlled patients must be at
some risk. Acetazolamide helps prevent AMS in asthmatic patients (Mirrakhimov et al. 1993).

273.2

Chronic obstructive lung disease

Chronic obstructive lung disease includes chronic

bronchitis and emphysema. Ventilatory capacity is
reduced and oxygen uptake impaired. If patients are
short of breath on exercise at sea level they will certainly be worse at altitude. Even mild cases will find
their performance markedly diminished at altitude.
The reserve capacity of the lung may be further
diminished by infection, and antibiotics should be
started at the first sign of an infective exacerbation.
Such patients should probably be advised to select
holidays which avoid high altitude. However, at
modest altitude patients with mild disease may have
no trouble. Roach et al. (1995) found that there
were no adverse signs or symptoms in their group of

Interstitial lung disease

Interstitial lung disease includes pulmonary fibrosis

from whatever cause, sarcoidosis, etc. In these conditions there is both restriction of the lung and interference with gas exchange. Altitude has a marked
effect on this aspect of lung function and patients will
find themselves much more short of breath. Cystic
fibrosis patients with bronchiectasis have problems
of both airways obstruction and gas exchange. One
paper describes two cases where an altitude holiday
appeared to tip the patients into cor pulmonale
(Speechley-Dick et al. 1992). In all but the mildest
cases they should be advised against going to altitude.
Cystic fibrosis patients with stable disease who are
proposing to go to altitude or indeed to fly in commercial aircraft can be tested in the laboratory by
breathing a hypoxic gas mixture (15 per cent oxygen
in nitrogen) for 10 min. The arterial oxygen saturation measured by a pulse oximeter gives a good indication of how they will fare at altitude (Oades et al.
1994). Other patients with stable lung disease might
also benefit from the test.
273.4
(HAPE)

High altitude pulmonary edema

A previous attack of HAPE indicates susceptibility

and the need for caution on future ascents. However,
many individuals have made subsequent ascents
without trouble, possibly because their one attack
was partly due to a respiratory infection. The prophylactic use of acetazolamide should be discussed
and nifedipine should be included in the first aid kit.

27.4
27.4.1

BLOOD DISORDERS
Anemia

Anemia, when oxygen carrying capacity is reduced,

should be treated prior to ascent. Premenopausal
women may have inadequate iron stores (Richalet et
al. 1994) and might benefit from iron therapy before
or during an excursion to altitude.

326 Medical conditions at altitude

27.4.2

Patients on anticoagulants

Patients with recurrent clotting or bleeding problems

may be taking unnecessary risks, but for those on
anticoagulants, if well controlled, there is no
increased risk from altitude per se but their being
remote from medical help will be a risk.

27.43

Sickle cell trait

Individuals with sickle cell trait may not be aware of

the problem. Reports in the literature indicate that
there is a 20-30 per cent risk that altitude travel over
2000 m may precipitate a crisis in patients with either
homozygous sickle cell disease (Hb SS), sickle
cell/hemoglobin C disease (Hb SC) or sickle cell trait
(Hb AS) (Adzaku et al. 1993). These crises are either
vaso-occlusive (mainly in Hb SS patients) or abdominal, splenic infarcts (mainly in Hb SC patients).
Two cases of white men with splenic crisis caused
by sickle cell trait have been reported at 2750 m. Both
were treated conservatively with satisfactory results
(Tierman 1999).

Insulin freezes at 0 C, so it should be kept warm

close to the body. Frozen insulin may be thawed out
without loss of potency, but care should be taken to
prevent breakage and spare ampoules carried.
Accidents to diabetics may be complicated by diabetic coma.
The companions of diabetic trekkers or mountaineers should be made aware of the problems that
diabetics face, should be able to recognize hypoglycemia and diabetic coma and know what to do in
emergencies. Hypothermia can produce hypoglycemia and exhausted diabetic mountaineers are at
considerable risk. Extra easily assimilated carbohydrates must be taken for bivouacs. Clearly insulin
dependent diabetes does present patients, their companions and trip leaders with problems. Many will
consider the risks of serious mountaineering at altitude to be unjustifiable. However, many diabetics on
well controlled insulin treatment have made successful, rather more modest trips to altitude. It is essential to discuss the situation with the expedition or
trek leader and doctor (if there is one) at an early
stage in planning.

27.6
27.5

GASTROINTESTINAL DISORDERS

DIABETES MELLITUS

Glucose tolerance is normal at altitude when energy

expenditure and food intake balance one another.
Exercise at altitude may improve sugar uptake and
for well controlled diabetics there appears to be no
contraindication to mountaineering.
Those taking insulin should appreciate not only
the considerable energy output that may be
demanded over a few days, up to 25 MJ (6000 kcal)
or more per day, but also the variation from day to
day and within the day. During severe exercise they
may need less insulin than on rest days because of
increased glucose uptake by muscle metabolism.
During rest days at altitude, insulin requirement will
be similar to that at sea level. Because of these great
variations diabetics should be encouraged to use
quick acting insulin, use three to four injections each
day and monitor the blood sugar closely.
Ready access to glucose in the form of sugar or
chocolate is necessary and for emergencies intravenous glucose should be available, as hypoglycemia
can be produced very rapidly by severe activity.

Intestinal colic and diarrhea are frequently encountered in mountainous areas but altitude per se is not a
factor. Simple traveler's diarrhea can be treated by
loperamide unless there is evidence of parasitic infection when specific medicine should be given.
The incidence of peptic ulcer appears to be less at
altitude (Singh et al. 1977). However, Wu (2000),
reviewing experience in over 5000 road workers in
Tibet, reported that gastrointestinal bleeding
10-70 days after arrival at altitude was not uncommon, with an incidence of 1-2 per cent.
Clearly, patients with known peptic ulcer should
be well controlled prior to the expedition as complications in the field can be fatal. Drugs such as nonsteroidal anti-inflammatory agents taken because of
joint problems or aspirin for headache may cause
gastric hemorrhage, which should be considered as a
cause of unexpected weakness. These drugs should
not be taken on an empty stomach.
Those with inflammatory disorders of the bowel,
such as Crohn's disease or ulcerative colitis in an
active phase, should not go on expeditions. An

Obesity 327

expedition, which lasts weeks or months, should be

considered very carefully for an individual in the quiescent phase and medication and diet planned to
ensure that the condition gets no worse. Adequate
treatment for an acute exacerbation must be available and evacuation of the patient should be easy.
Hemorrhoids, perianal hematoma and fissure-inano are often considered trivial conditions except by
sufferers. They are not, and pre-expedition treatment
must be undertaken. On an expedition a prolapsed
pile should be replaced as soon as possible; perianal
hematoma is classically a self-limiting condition lasting 5 days before resolution, but the clot may be
evacuated under local anaesthetic. Acute fissure-inano may be exquisitely painful. Anesthetic ointment
should always be available and, if necessary, a fissurotomy may be carried out under local anesthetic.
Any recurrent perineal or ischiorectal abscess must
be dealt with prior to an expedition, as must fistulae
and pruritus ani. Abscesses can be drained in the
field, but even when an adequate anesthetic is available this is painful postoperatively.
Patients with hernias must have these repaired
prior to an expedition. Any hernias occurring in the
field should be reduced and kept reduced by a homemade truss. Irreducible and strangulated hernias can
be and have been operated on under local anesthetic,
and the simplest operation consistent with the operator's skill and the patient's condition should be carried out.
Patients with recurrent appendicitis should consider an appendectomy prior to an expedition. In the
past prophylactic appendectomy has been advised
before very long periods away from good medical
cover, but this is not necessary. If appendicitis occurs
during an expedition it should be treated conservatively with antibiotics, intravenous fluids and
nothing by mouth. Often it resolves; if an abscess or
appendix mass forms this may either resolve or it will
point on the abdominal wall or rectum and can be
drained. Ruptured appendix and peritonitis should
be drained under local anesthetic.

27.7

ORTHOPEDIC CONDITIONS

Those with arthritis, particularly of the joints of the

lower limb, should carefully consider the degree and

amount of exercise that has to be taken on a mountain trek. Nonsteroidal anti-inflammatory drugs can
be very beneficial and should be started early rather
than being heroic about the pain. Treatment of
painful joints, particularly of the hip, whether by
replacement prosthesis, arthrodesis or some other
method, may make a short trek possible. One member of the successful Everest 1953 expedition who
climbed to 8500 m had a fixed flexed elbow, the
result of an accident as a child.

27.8
ENT CONDITIONS AND DENTAL
PROBLEMS
Nasal polyps or a deflected nasal septum, which
interferes with breathing, should be treated prior to
ascent. Patients with perennial rhinitis and sinusitis
should ensure supplies of their usual medication.
Dental problems theoretically are not made worse
by altitude but in practice dental abscesses seem to
be quite common. Anyone planning a holiday or
expedition out of range of dental help on the mountains or anywhere else, is well advised to have a
thorough dental check up and any suspect teeth dealt
with before setting out.
A case of HAPE following root canal infection
has been reported. This was successfully treated
by descent, antibiotics and appropriate surgery
(Finsterer 1999).

27.9

OBESITY

Obesity has been reported as being a risk factor for

AMS (Chapter 18) and the overweight will have an
increased oxygen uptake for a given task. At night
obese individuals may suffer from a greater fall in
arterial P02 as the weight of the abdomen interferes
with normal lung expansion. The repeated episodes
of hypoxemia lead to increased pulmonary hypertension. In addition, they are more likely to have
sleep disorders with, in particular, obstructive sleep
apnea during which the arterial P02 can fall precipitously. In residents at altitude this may cause an
undue increase in red blood cells and may be implicated as a cause of chronic mountain sickness
(Chapter 21).

328 Medical conditions at altitude

27.10

27.10.1

NEUROLOGICAL PROBLEMS

Headache

Headaches are common on ascent to altitude, probably because of mild cerebral edema. These are
features of AMS and resolve spontaneously in a few
days. There is anecdotal evidence that altitude tends
to trigger migraine attacks which can be severe. One
sufferer had an attack of transient nominal aphasia at
5500 m. A history of migraine is a risk factor for AMS
(Chapter 18).

27.10.2

Epilepsy

There is no evidence that epileptics are worse off or

that fits are more frequent at altitude. However, the
consequences of an epileptic attack need to be considered both on affected individuals and on their
companions. Understanding this, it is probably reasonable for patients with well controlled epilepsy,
who have not had a fit for 6 months, to go on a trek
but not to undertake rock or ice climbing. Some
antiepileptic preparations may affect breathing
adversely during sleep, and others in high doses may
affect coordination.

27.10.3

Sleep

Nightmares and vivid dreams are not unusual at altitude and sleep may be very disturbed. Those who
take drugs at sea level to induce sleep should remember that these often depress respiration and can lead
to severe transient hypoxia. In any event, sleep at altitude is usually lighter and often less refreshing than
at sea level (Chapter 13).

27.11

MENTAL OUTLOOK

Mountaineering is a potentially dangerous sport with

an appreciable mortality. It requires time and
patience to master all the skills necessary to move

safely in mountain country, which is no place for the

danger-mystic with or without religious overtones.
Mental agility and emotional stability are important and the gregarious extrovert who can only be
effective with constant activity and an impressionable audience is not so likely to function effectively as
the more self-sufficient. Those who are obliged to
live harmoniously in close proximity for long periods
should be stable, loyal and have both a social and
intellectual tolerance for their companions. Above
all, a sense of humor and the ability to control and
sublimate hostile and aggressive impulses are of great
importance.
Considerable attention has been paid to the possible effects of emotional deprivation, with reference
to sexual abstinence, in isolated single-sex communities. Most agree that sexual deprivation is usually of
minor significance and, as a subject of conversation,
ranks rather lower than food, drink or the task in
hand. At high altitude reduction in libido has been
reported in some lowlanders. High altitude residents
do not appear to be affected. Instructions on the frequency of sexual intercourse are included in a work
on traditional Tibetan medicine: 'During winter one
can indulge in intercourse twice or thrice daily, since
sperm increases in winter. In the autumn and spring
there must be an interval of two days, and during the
summer an interval of 15 days. Excessive intercourse
affects the five sense organs' (Rinpoche 1973,
pp. 54-5). Elderly, enfeebled Tibetans drank the
urine of young boys to increase their sexual vigor
(MacDonald 1929, p. 184).
For the majority of people, venturing into the high
mountains is a wonderful experience even if, at
times, the conditions are harsh and uncomfortable.
Most have graduated via family trips into the hills,
short camping trips near home, hill walking, etc., but
some suddenly get the idea that they want to embark
on some big trek or expedition with no previous
experience and have quite unrealistic ideas of their
own performance. Sometimes all works out well and
they adapt to what is a very different lifestyle with no
problem, but others are clearly psychologically quite
unsuited to it and become psychiatric casualties, to
the distress of themselves and their companions.

28
Women, children and elderly people
at altitude
28.1
28.2

Introduction
Women

330
330

SUMMARY

Women respond to altitude in very much the same

way as men. They acclimatize in a similar way and are
as likely to get acute mountain sickness (AMS). Their
exercise performance is similarly affected by altitude.
Recent studies into the effect of the menstrual cycle
have failed to find significant differences in performance or susceptibility to AMS in different phases of
the cycle. Women seem to have an advantage over
men in that they lose less weight at altitude, probably
because they suffer less loss of appetite. The risk of
altitude in pregnancy is not known but in the present
state of knowledge women in the early stages of
pregnancy are advised not to go beyond moderate
altitudes. This is because of the possible risk of
hypoxia on organogenesis in the fetus and likely
discomfort for the mother in later pregnancy. Oral
contraceptives (the pill) are widely used for both
contraception and for menstrual regulation by
women at altitude. Although there is the theoretical
risk that altitude and increased hematocrit may lead
to thrombosis, there is no direct evidence that this is
the case.
Children are at risk at altitude if they are too young
to be able to voice their symptoms of AMS which
then may not be diagnosed promptly. Any child who
has recently ascended to altitude and becomes unwell

28.3
28.4

Children
Elderly people

331
334

must be assumed to be suffering from AMS unless

there are clear signs of an alternative diagnosis.
Children are as likely to get AMS, high altitude
pulmonary edema (HAPE) and high altitude cerebral
edema (HACE) as adults are. The management of all
forms of AMS is similar to that in adults with
appropriate adjustment of dosage of drugs. Children
are more at risk of hypothermia and cold injury
because of their larger surface to weight ratio and
especially if they are being carried and not exercising.
Infants are at risk of subacute mountain sickness if
they remain at altitude for months. The justification
for taking young children to altitude is questionable
and is discussed.
Increasing numbers of elderly people are going
on holidays to the mountains. If they are otherwise
fit, age is no bar to enjoying such holidays. Their
exercise capacity will be less than that of younger
mountaineers and their goals must be adjusted
accordingly. With age comes the likelihood of
various medical conditions, especially heart and
lung disease, which may interfere with performance
at altitude. However, the risk from occult disease,
specifically asymptomatic coronary artery disease, is
very small. Elderly are no more likely to get AMS
than young people, indeed in practice they seem
to suffer less, perhaps because they are likely to
gain altitude more slowly or they may be less
susceptible.

330 Women, children and elderly people at altitude

28.1

INTRODUCTION

Until recently, studies of the effect of altitude on

humans have used fit young men as their subjects.
There have been few studies addressing the question
of the effect of altitude specifically on women,
children or elderly people. In the last few years this
deficiency has been repaired to some extent in the
case of women but we have very few hard data on
children or elderly people. Such studies as have been
published are reviewed in this chapter but in trying
to provide answers to frequently asked questions we
still have to rely often on anecdote or extrapolation
from inadequate data. This chapter deals mainly with
lowland women, children and elderly people going to
altitude, highland populations being the subject of
Chapter 17.

28.2

28.2.1

WOMEN

Introduction

In 1970 the Japanese climber Setuko Wanatabe was

the first woman to climb Everest; since then, women
of many nationalities have also made the ascent,
some without the use of supplementary oxygen.
Women have climbed other 8000 m peaks including
K2 and Kangchenjunga without added oxygen, and it
will probably not be long before someone claims the
record of the first woman to climb all 14 8000-m
peaks. By the end of 1999 there were 54 ascents of
Everest by women (Unsworth, 2000).
Clearly women can acclimatize and perform at altitude as well as most men, even if there are fewer women
in the elite category. In this section the differences in
physiology between women and men will be discussed
though, as women's achievements demonstrate, similarities are probably greater than differences.

28.2.2

Acclimatization

Women acclimatize in a similar way to men. In

respect of respiratory acclimatization their increase
in ventilation in response to chronic hypoxia was
documented as long ago as 1911 by Mabel FitzGerald
(FitzGerald 1913). She measured the alveolar Pco2 of
acclimatized men and women over a range of

altitudes and showed that the PACC,2 is about

2 mm Hg less in women than in men. Their P02 1S
correspondingly slightly higher. Others, including
Hannon (1978), have confirmed this finding and
Barry et al. (1995) found, using arterialized capillary
blood, that Pco2 fell more in women than in men
during acclimatization, as did their bicarbonate.
Women's greater ventilation at all altitudes is
assumed to be due to the stimulatory effect of sex
hormones and disappears after the menopause.
Women increase their hemoglobin concentration,
hematocrit and red cell mass in the same way as men
in general, though some women fail to do so because
their iron stores are low as a consequence of their
menstrual blood loss. Richalet et al (1994) reported
two such cases in their study on Samaja in Bolivia and
documented their low iron stores. It was also shown
that their erythropoietin response was good. In an
early study on Pikes Peak (4300 m) in Colorado
(Hannon et al. 1966) it was shown that women on
iron supplements had rises in hemoglobin concentration similar to men whereas women not taking iron
had a slower increase in hemoglobin concentration.
If susceptibility to AMS is seen as slow acclimatization then, again, there is probably no significant
difference between men and women.

28.2.3
cycle

Performance and the menstrual

Beidleman and colleagues (1999) tested the possibility that the effect of hormones in the midluteal
phase of the menstrual cycle on exercise ventilation
might improve oxygen transport especially at
altitude. They undertook a chamber study at sea level
and 4300 m equivalent in eight female subjects,
testing them in their early follicular and midluteal
phases. They found that there was no difference
between the phases for peak and submaximal
exercise ventilation. Sa02 was 3 per cent higher at
altitude during the midluteal phase but Vo2max and
time to exhaustion were no different between phases
at sea level or altitude.

28.2.4

Weight loss

Women seem better able to maintain their weight on

going to altitude than men do. In a group of women
studied on Pikes Peak (4300 m) Hannon et al. (1976)

Children 331

found that they lost only 1.49 per cent of their body
weight compared with 4.86 per cent in a group of
men. This was attributed to the fact that the women
seemed to regain their appetites sooner than the men
did. Collier et al. (1997b) also found less weight loss
in a group of women trekkers to Everest Base Camp
(5340 m). The women had no significant weight loss
during their stay at this altitude, while the men lost
an average of 0.11 kg m-2 day-1. In seven men who
climbed to altitudes of 7100-8848 m the weight loss
averaged 0.15 kg m-2 day-1 whereas the one woman
who climbed to above 8000 m lost no weight.
28*2.5 Catecholamines and
carbohydrate metabolism
In a 12-day study on Pikes Peak (4200 m) Mazzeo et
al. (1998) found no difference in catecholamine
response between men and women or between the
follicular and luteal phases of the menstrual cycle.
However, for a given norepinephrine urinary excretion the heart rate and blood pressure response were
lower in the follicular than in the luteal phase.
As mentioned in section 15.8, sensitivity to insulin
appears to be increased at altitude in men. Braun et
al. (1998) found that after 9 days at altitude (4300 m)
the blood glucose response to a standard meal was
reduced in women, possibly due to increased stimulation of peripheral glucose uptake or suppression of
hepatic glucose production. They found that the
glucose response was lower in the estrogen phase
than in the estrogen plus progesterone phase of the
menstrual cycle.
In a recent study Mawson et al. (2000) found that
the total energy requirement of women at 4300 m
was 6 per cent above sea level values. Although there
was a transient rise in basal metabolic rate (BMR)
this did not explain all the increase. Unlike men,
blood glucose utilization rates in young women after
10 days at 4300 m were lower at rest and no different
during submaximal exercise from those observed at
sea level. There was no correlation with circulating
estrogens or progesterone (Braun et al. 2000).
28.2.6 Pregnancy and oral
contraceptives
The risk to a pregnancy of going to altitude is not
known with confidence, but it seems wise to advise

pregnant women against ascent to more than a

modest altitude. In the early months of pregnancy,
during organogenesis, there is the risk that hypoxia
might result in fetal abnormalities. Later in
pregnancy the increased bulk of the uterus and raised
diaphragm will make for discomfort in the mother
and interfere with her breathing.
There are no data on the risk of using oral contraceptives at altitude but it is well known that they
increase the risk of thrombosis at sea level. However,
the risk is less in current formulations and is even
smaller in nonsmokers. The increased hematocrit at
altitude and dehydration, should it occur, may
increase this risk. After some weeks at altitude
vascular episodes, some thrombotic in nature, have
been reported, though not in women. A recent
survey (Miller 1999) of 926 trekkers on the Everest
Base Camp route found that of 316 women,
30 per cent were using an oral contraceptive, mostly
for control of menstruation. A significant number
did report irregularities of menstruation especially if
pills were not taken regularly, but there were no
medical complications. However, though reassuring,
the numbers were too small to draw firm conclusions
regarding safety. A discussion of this question can be
found in the International Society of Mountain
Medicine Newsletter (ISMM 1998). In earlier editions
we advised against the use of the pill. Clearly women
are using it, and the advice now should be that if used
it should be taken regularly.
28.2.7

Women and cold

Cold injury, hypothermia, frostbite and immersion

injury are seldom reported in women at altitude. A
factor may be the relatively thicker layer of subcutaneous fat found in women. It is also possible that
women are more meticulous in their preparation for
cold conditions and so avoid cold injury through
negligence.

28.3
28.3.1

CHILDREN
Introduction

The increased accessibility of the high altitude

regions of the world to adults means that more
children are now being taken on adventure holidays

332 Women, children and elderly people at altitude

to these places. Even infants have been carried over

6000 m peaks in Nepal (Pollard et al. 1998). Are these
children at risk from the effects of altitude? What
advice should a doctor give to parents considering
taking children to altitude?

283.2

Diagnosis of A MS in children

In older children, the diagnosis of AMS can be made

on symptoms as in adults. The diagnostic problems
are much the same. Those feeling cold, miserable and
depressed may exaggerate while those (usually boys
in a group) who consider it 'sissy' to admit to
symptoms will minimize them. However, in younger
children who cannot articulate their feelings the
problems are worse. In them AMS symptoms cannot
be distinguished from other causes of ill health. In
the setting of a recent increase in altitude, the only
safe course is to assume a young child's fractiousness
is due to AMS unless there are signs clearly pointing
to some other cause. Yaron et al. (1998) have
proposed a 'fussiness score' in such preverbal
children, analogous to the Lake Louise score for AMS
(section 18.8). They studied 23 children aged 3-36
months in Colorado at Denver (1609 m), Fort
Collins (1615 m) and Keystone Summit Lodge
(3488 m), taking 4 days to reach there. There were 45
accompanying adults and 20 per cent of these had
AMS at Keystone. Using their score, 21 per cent of
the infants were diagnosed as having AMS. Fussiness
is scored on a scale of 0 to 6 for both amount and
intensity. This equates to the headache symptom.
Other symptoms are then scored 0 to 3 for, 'How
well has your child eaten?', 'How playful is your child
today?' and 'How has the child napped today?'.

2833

Incidence of AMS in children

There have been a few surveys of children at altitude.

Wu (1994b) studied adults and children as they
travelled the Qinghai-Tibet highway to Lhasa. He
surveyed 5355 adults and 464 children at the
overnight stop, Tuo-Tuo (4550 m). These people
were lowland Han Chinese. The diagnosis was made
on symptoms and on the response to oxygen breathing. HAPE was also diagnosed by chest radiograph.
The incidences for AMS and HAPE respectively were
38.2 per cent and 1.27 per cent in adults and
34.1 per cent and 1.51 per cent in children. In

Colorado Theis et al. (1993) found an incidence of

AMS of 28 per cent at an altitude of 2835 m for children aged 9-14 years, but there was no comparable
figure for adults. This may seem rather high for this
altitude but a control group at sea level had a
20 per cent incidence of these symptoms, so some
may have been due to the travel itself. From these
studies (including that of Yaron et al. (1998) above)
it would seem that children probably have about the
same susceptibility to AMS and HAPE as adults. One
paper also suggests that, as in adults, respiratory
infection predisposes to HAPE in children
(Durmowicz et al. 1997).

283.4

Management of AMS in children

The management of AMS in children is the same as

in adults (section 18.7). The crucial first step is to
have a high index of suspicion in the setting of a
recent gain in altitude. The essential step is to get the
child down to a lower altitude. Only in the mildest
cases is a 'wait and see' policy justified. If there is any
suspicion of AMS further ascent is out of the
question. There have been no formal trials of any
drugs in children in this setting but it is assumed that
the same medication can be used in children as in
adults. The dosage suggested for drugs used in AMS
is shown in Table 28.1.
The management of HAPE and HACE is similar to
that in adults (Chapters 19 and 20). There is a report
of the successful use of the Gamow bag in a 3.5-yearold child with severe AMS (Taber 1994).

283.5

Infants at altitude

There are some special considerations that apply to

infants at altitude relating to the immaturity of their
respiratory control mechanisms and the fact that
their pulmonary arteries are undergoing involution
of the thick muscular layers at this time.
In the neonate, hypoxia has a depressant effect on
ventilation. Normally this reverses to the adult
pattern of stimulation in the first few weeks of life,
but a study by Parkins et al. (1998) found that even at
3 months infants responded to 15 per cent oxygen
breathing by frequent periods of isolated and
periodic apnea. The mean saturation on 15 per cent
oxygen was 92 per cent in these infants. The
responses were very variable, but some infants had

Children 333
Table 28.1 Dosage for drugs used in children for AMS, HAPEand HACE

Paracetamol
Dexamethasone
Acetazolamide
Nifedipine

12 mg kg~1 dose 6 hourly

0.15 mg kg-1 dose 4 hourly
5 mg kg-1 8-12 hourly, max 350 mg
0.5 mg kg-1 dose 8 hourly,
max 20 mg for caps, 40 mg for tabs

Oral
Oral or i.v.
Oral
Oral

Aspirin should be avoided because of the slight risk of Reye's syndrome.

Source: after Pollard and Murdoch (1997).

saturations which fell to less than 80 per cent for up

to a minute (at which time the intervention was
stopped). This response must be part of the mechanism of infantile subacute mountain sickness (Sui et
al. 1988) described in Chapter 22.
The question of risk of sudden infant death
syndrome (SIDS) at altitude has been addressed in
one study. It might be thought that altitude could be
an added risk factor for SIDS. Kohlendorfer et al.
(1998) carried out a case control study in Austria of
SIDS deaths. They found that higher altitude districts
did have higher rates of SIDS but these districts also
had higher rates for the practice of placing infants in
the prone position for sleep. This effect largely
accounted for the difference in rate of SIDS. The
possibility that altitude has some risk for SIDS
cannot be ruled out, especially at altitudes higher
than in this study.

28.3.6

Children, cold and heat

Children are not only smaller than adults but have a

larger surface to weight ratio, so as a result cool faster
in cold and heat up more quickly in hot conditions
(Kennedy 1995). Thermal balance is less efficient in
children, and during exercise they generate more
metabolic heat for a unit mass than adults, have
lower cardiac output and gain heat more rapidly
from the environment. They also acclimatize to heat
more slowly in hot conditions. In addition to their
larger surface to mass ratio, they have less subcutaneous fat and may have an underdeveloped
shivering mechanism. For all these reasons, they are
at greater risk than adults of hypothermia in a cold
environment and of overheating in hot environments.
In cold or wet conditions a windproof and water-

proof garment is essential, and particular attention

should be paid to the head from which proportionally more heat is lost than in an adult. It should also
be remembered that a child who is being carried is
not generating heat in the way the adult carrier is and
so needs more clothing.
Overheating can occur when on a glacier or
snowfield in sunny conditions because of direct
and reflected heat. Eyes must be protected by
goggles and the exposed skin by sunblock cream.
Adequate fluid must be given, especially in hot
conditions, to prevent dehydration (Pollard and
Murdoch 1997).

283.7

Conclusions

Although children are at no greater risk of AMS than

adults at the same altitude, the fact that young
children have difficulty in articulating their
symptoms means that diagnosis is more difficult and
may be delayed. The fact that in most cases an
altitude holiday is also a holiday in a part of the world
where medical help is far away and gastrointestinal
infections and other diseases are common must be
borne in mind. Also it is true that children with these
problems can progress from being perfectly healthy
to being seriously ill at an alarming rate. Finally, it is
questionable if young children really appreciate the
mountain environment in the way adults do, so the
rewards of such a holiday, as compared with a more
conventional bucket and spade or low altitude
country holiday, are less. On the other hand family
travel is undoubtedly a valuable experience. On
balance we would concur with Pollard et al. (1998) in
a cautious approach in advising families considering
high altitude trips. They suggest that, with children
under 2 years of age, parties should not sleep at over

334 Women, children and elderly people at altitude

2000 m and no higher than 3000 m for children of

2-10 years. The latter may be too conservative since
children of say 6-10 years who can express their
symptoms could well enjoy higher altitudes with
probably little more risk than adults.

28.4

28.4.1

ELDERLY PEOPLE

Introduction

The increased numbers of people going to high

altitude, mainly for recreation, include a large
proportion of elderly people. Many retired men and
women have both the money and time to enjoy treks
to the great ranges, to ski and to attend conferences.
Doctors are often asked questions about risks
involved. In Chapter 27 specific pre-existing conditions are considered which are more frequently
encountered in elderly patients. In this section we
consider the apparently fit elderly person at altitude.
The effects of altitude on cardiovascular and
pulmonary problems have been studied in elderly
people, and a survey of over 1900 visitors to
Keystone, Colorado (2783m), revealed that
48 per cent were aged 40-60 years and 15 per cent
were over 60. Approximately 10 per cent of trekkers
in Nepal were 50 years of age or older (Hultgren
1992) and a few mountaineers of this age have
climbed Everest using supplementary oxygen
(Gillman 1993).

28.4.2

Performance

All bodily functions deteriorate with age and this

includes the maximum oxygen uptake both at sea
level and at altitude (Pugh et al. 1964). However, the
effect of age on V^max is very variable (Dill et al.
1964). West et al. (1983c) reported the results of
measurements of V0 max on two subjects. There was
only a moderate deterioration in performance over a
20-year period (aged 31-51 years). Ability to go to
altitude depends more on an individual's degree of
fitness than on age. Fit men of 75 years who normally
live at sea level have spent months at 5000 m without
difficulty and a peak of 6000 m has been climbed by
an 80-year-old mountaineer. However, their ability
to carry loads is reduced. No one should be discouraged from going to altitude on grounds of age alone,

but rapid ascent and undue exertion will place more

strain on those in the older age group than on those
who are younger. However, their greater experience
will enable them to pace themselves so that given
time they can often achieve worthwhile objectives.
Levine et al. (1997) studied 20 subjects with a mean
age of 68 years attending a veterans' reunion at a
resort at 2500 m. They found the expected decrease
in Pa0l, Sa02 and V 02max and increase in pulmonary
artery pressure of 43 per cent associated with sympathetic activation. The induction of a 1 mm depression of the S-T segment occurred at a lower exercise
rate at altitude but this returned to sea level values
after 5 days at altitude. They conclude that elderly
men acclimatize well at this altitude and retain sea
level performance after 5 days.

28.4.3

Age and AMS

It might be assumed that older people would be more

prone to AMS, but there is no evidence that this is the
case. Anecdotal evidence suggests that older
mountaineers do better than the young but this may
be because they do not climb so fast and therefore are
at lower risk of AMS. Also there could be selection
bias - poor acclimatizers do not go back to the
mountains later in life. Surveys such as that by Kayser
(1991) find no significant age effect on the incidence
of AMS. Although it is true that older people have
more pre-existing disease, especially heart and lung
disease, it seems that this does not increase the risk of
AMS (Roach et al. 1995); nor does the fact that with
age the sensitivity of the ventilatory response to
carbon dioxide and to hypoxia decline (Kronenberg
and Drage 1973, Poulin et al. 1993).

28.4.4

Conclusions and advice

The evidence that we have indicates that age alone is

no bar to a fit person going to altitude. Exercise
capacity is reduced in elderly people as in young
people, and the itinerary planned accordingly, but
the risk of AMS is no greater. However, 'age never
comes alone' and the presence of pre-existing
conditions which might reduce one's enjoyment of a
holiday at best and be life threatening at worst should
give pause for thought. Some of these conditions are
considered in Chapter 27. However, anyone who can
manage a full day walking on hills at low altitude

Elderly people 335

without undue strain is likely to be able to enjoy a

standard Himalayan trek. In a situation of having to
go rapidly to altitude, for instance having to fly into
an airport at high altitude, it is probably more

important for elderly people than for young people

that they should give themselves 2-3 days to
acclimatize before undertaking any strenuous
activity (Levine etal. 1997).

29
Commercial activities at altitude
29.1 Introduction
29.2 Historical
29.3 Mining

336
336
337

29.4 Telescopes
29.5 Oxygen enrichment of room air to relieve
the hypoxia of high altitude

340
341

SUMMARY

29.1

Increasingly, large numbers of people are commuting to high altitude for commercial and scientific
activities. Several mines are now situated at altitudes of 4000-6000 m. In some cases, the miners
live at sea level and are bussed up to the mine
where they spend 7 days, then return to their families at sea level for a further 7 days, and the cycle is
repeated indefinitely. This pattern raises interesting
questions about acclimatization. In addition, studies are in progress to try to determine how best to
select people for this work. Telescopes are being
sited at an altitude of 4200 m in Mauna Kea
(Hawaii), and even higher at 5000m in Chajnantor
in north Chile. In Mauna Kea, some of the workers commute daily from sea level. For the
Chajnantor project, many workers will live at an
altitude of 2400 m and commute to the telescope
though some will sleep at 5000 m. An important
innovation is the use of oxygen-enriched rooms at
high altitude to reduce the equivalent altitude.
Each 1 per cent increase of oxygen concentration
reduces the equivalent altitude by 300 m. Oxygen
enrichment has been shown to improve neuropsychological function during the day and enhance
sleep at night. The use of oxygen-enriched modules
at the Chajnantor site shows great promise.

Currently one of the most challenging and interesting

topics in high altitude medicine and physiology relates
to the increasing number of people who commute to
high altitude for commercial or scientific activities.
The two main areas are high altitude mining and high
altitude astronomy. Mining at high altitude goes back
several hundred years, although the modern practice
of having miners commute from much lower altitudes, even sea level, is relatively recent. Siting telescopes at high altitudes, for example over 4000 m, is
also a more recent activity. Some of the most interesting problems arise in connection with placing telescopes at an altitude of 5000 m in north Chile.
This chapter overlaps somewhat with two previous chapters. The value of oxygen enrichment of
room air to improve sleep at high altitude was briefly
discussed in Chapter 13. The improvement of neuropsychological function at an altitude of 5000 m as a
result of oxygen enrichment of room air was referred
to in Chapter 16.
29.2

INTRODUCTION

HISTORICAL

Mining activities at high altitude are very old. Gold

has been mined in west Tibet for centuries. The

Mining 337

open cast mines at Thok Jalung (Thok is Tibetan for

gold) were investigated in 1867 by Nain Singh, one
of the early pundits, secret native explorers of the
Survey of India (Waller 1990). Chinese sources suggest that Tibetans worked at 6000 m in the Tanggula
range of central Tibet mining quartz, and chromate
mines are also found in central Tibet (Ward 1990).
In several areas of the South American Andes, there
is evidence that mining activities were carried out by
the Incas before the Spanish conquest. The Spanish
conquistadors founded the imperial city of Potosi
(4060 m) in Bolivia, the site of an enormous silver
mine, in the 1540s. According to one historian
quoted by Monge, M. (1948) when the city was
founded there were 100 000 natives and 20 000
Spaniards. However, little information remains
about the actual mining activities.
A very informative account of the mining practices
in Cerro de Pasco, Peru (4340 m), was given by
Barcroft et al. (1923) in their account of the
International High Altitude Expedition to Cerro de
Pasco which took place in 1921-2. Although most of
the studies carried out by the physiologists were on
themselves, many interesting observations were
made on the native miners. One mine was 250 ft
(76 m) below the surface, and the staircase which led
down to it was 600 ft (183 m) in length. The porters
who carried up the loads of ore from the mine varied
greatly in age and stature. One boy who was said to
be 10 years of age carried a load of 40 Ib (18 kg)
(Figure 29.1). Another porter who was thought to be
19 years old brought up a load of about 100 Ib
(45 kg). The physiologists noted that the exercise was
spasmodic. The climb was very slow and consisted of
the ascent of a few steps, followed by a long pause
during which the porter regained his breath. They
noted that the panting of the porters could be heard
far down the staircase, before they came into view.
The miners enjoyed sports, for example soccer, when
they were not working. Each period of the game was
15 min long.
More recently, the extraordinary physical activity
of miners at the Aucanquilcha mine (5950 m) in
north Chile has been described (Mclntyre 1987). The
photograph on page 455 of that article shows the
miners shattering boulders of sulfur ore using sledgehammers. The caretakers of this mine lived indefinitely at this altitude, and they were probably the
highest inhabitants in the world (West 1986a). The
mine is no longer working.

Figure 29.1 Photograph from the report of the 1921-2

International High Altitude Expedition to Cerro de Pasco, Peru,
showing a young boy, said to be 10 years old, carrying a load of
18 kg, which he has just brought up from the mine 250 ft (76 m)
below the surface. (From Barcroft et al. 1923.)

293

MINING

Table 29.1 lists the altitudes of some of the most

important commercial activities at high altitude. All
of these are mines, except for two telescope sites. It
can be seen that many of the mines are above 4000 m
in altitude, with the highest being Aucanquilcha at
5950 m, although, as indicated earlier, this mine is no
longer operating.
The mines fall into two categories. Many of the old
mines, such as those at Cerro de Pasco and
Morococha, have complete communities near the
mine itself. This means that the families are located
there and, in particular, the children are raised at
these high altitudes. Many people question the wisdom of this because there is some evidence that children grow more slowly at high altitude (Frisancho
and Baker 1970), although the issue is somewhat
controversial. Certainly the central nervous system is

338 Commercial activities at altitude

Table 29.1 Examples of commercial and scientific activities at altitudes of 3500-6000 m

Chile

Peru
Bolivia
Hawaii
Colorado

Andina
Aucanquilcha3
Choquelimpie
Collahuasi
El Indio
Quebrada Blanca
Chajnantor
Cerro de Pasco
Morococha
Potosi
Mauna Kea
Climax
Summitville

3400-4200
5950
4500
4400-4600
3800-4000
4400
5000
4330
4550
4060
4200
4350
4050

33S
21S
20S
21S
30S
21 S
23S
11S
12S
20S
20N
39N
37N

Copper
Sulfur
Silver
Copper
Copper, gold, silver
Copper
Telescope site
Copper, gold, lead, zinc
Copper
Silver, tin
Telescope site
Molybdenum
Gold

' This mine is not operating at present.

exquisitely sensitive to hypoxia, as discussed in

Chapter 16, and, other things being equal, one would
prefer to see children brought up in a more normal
ambient P0r
Another disadvantage of having whole communities at the site of the high altitude mine is that a large
amount of infrastructure has to be provided. This
includes schools, medical facilities and meeting halls,
all of which increases the expenses of the mine. These
considerations have led many modern mining operations to develop a commuting pattern where the
families live at or near sea level and the miners commute to the mine itself where they spend a period of
7-10 days.
As an example of a modern mine based on the
commuting pattern, the new mine at Collahuasi will
be briefly described. This is a very large, open-cut
copper mine in north Chile at a latitude of 21S.
Mining operations in this area were carried out in
pre-Spanish times. It is interesting that Thomas H.
Ravenhill (1881-1952), who gave the first accurate
clinical descriptions of high altitude pulmonary
edema (HAPE) and high altitude cerebral edema
(HACE) (Ravenhill 1913), was the medical officer at
this mine in 1909-11 (West 1996b). The working
areas of the mine are at altitudes of 4400-4600 m,
though the mining camp where the miners sleep is at
an altitude of 3800 m. There are currently several
thousand people working at the mine, which makes
it one of the largest copper mines in the world.
Copper is a major export of Chile.
The miners' families live in Iquique on the coast in

accommodation supplied by the mining company.

The miners are transported to the mine by special
buses which take a few hours for the trip on a new
road built by the mining company. A typical schedule is that the miners spend 7 days at the mine, where
they work for up to 12 h per day, and then sleep in
the mining camp at an altitude of 3800 m. At the end
of 7 days they are bussed down to Iquique, where
they spend the next 7 days with their families. The
cycle is repeated indefinitely.
This pattern raises many questions for which
answers are not presently available. For example, it is
not clear to which altitude the miners will be acclimatized. Since they oscillate between sea level and
4400-4600 m every week, they presumably will not
fully acclimatize to either altitude. In this respect,
they have some similarities with the railway crews
who shuttle between Lima and the high Andes
(Hurtado et al. 1945). On the other hand, it is likely
that the mine workers tolerate the altitude of the
mine much better than would be the case if they
came straight from sea level with no previous exposure to altitude. An interesting anecdotal fact is that
when these miners return to their families at sea
level, they complain of being very 'tired' for the first
couple of days. A common joke has it that any children are conceived on the third night of return.
The 7 by 7-day schedule referred to above is not
universally employed in the high altitude mines that
use commuting. Periods at high altitude as long as
10-14 days have been tried. It clearly does not make
much sense from a physiological point of view to

Mining 339

have a period at high altitude of less than 7 days

because there is evidence that the ventilatory
acclimatization continues for at least this period of
time (Lahiri 1972, Dempsey and Forster 1982).
Other features of high altitude acclimatization, such
as the development of polycythemia, take several
weeks to reach a steady state. On the other hand, the
physiological value of polycythemia is unclear
(Winslow and Monge C. 1987).
Another important question is the rate of deacclimatization. Ideally, the workers should not lose
all the acclimatization that they have developed at high
altitude during their period with their families at sea
level. Relatively little information about the rate of
deacclimatization is available, although some measurements suggest that the rate of change of the
ventilatory response during deacclimatization is
slower than during acclimatization (Lahiri 1972).
Deacclimatization is discussed further in section 4.4.4.
Finally, although the physiological aspects of
scheduling are important, it may be that social factors will be dominant. Experience has shown that
miners are reluctant to leave their homes for more
than 7-10 days, and it is probable that a schedule of
7 days of high altitude followed by 7 days at sea level,
or alternatively 10 by 10 days, will be the most
acceptable.
Reference was made above to the miners at
Aucanquilcha (5950 m) breaking large pieces of sulfur ore using sledgehammers. However, the activities
at a modern mine such as Collahuasi are quite different. The ore is dislodged using explosives, and then it
is picked up by enormous diesel electric front-end
loaders that can scoop up 80 tons of ore at a time.

Three scoops are then placed in an gigantic diesel

electric truck, which can carry 240 tons (Figure 29.2).
Of course, considerable skill is necessary to operate
these very large pieces of equipment, and substantial
damage can be done to people or machines if the
equipment is not operated correctly.
The highly skilled nature of modern mining is one
reason why, in mines like Collahuasi, none of the
miners are people indigenous to the high altitudes.
Another reason is that there is not a large indigenous
high altitude population in Chile. This is in contrast
to the situation in many mines in Peru where, for
example at Cerro de Pasco and Morococha, there are
large indigenous populations who can provide relatively cheap, unskilled labor for the mines.
Another challenging problem of these high altitude mines is the selection of workers. Certainly not
everybody is able to work effectively at altitudes of
4400-4500 m. There is considerable interest in possible medical tests that could predict who will be able
to work well at altitude or, perhaps more important,
who will be unable to tolerate the altitude. One possible test is the ventilatory response to hypoxia, during both rest and exercise (Rathat et al. 1992). As
pointed out in Chapter 12, there is evidence that tolerance to extreme altitude requires a reasonable level
of hypoxic ventilatory response in order to defend
the alveolar P02 at a viable level. However, whether
this will be a useful prognostic test for working at
altitudes of 4000-5000 m is not clear. Probably the
best predictor at the present time is whether a
prospective worker has previously worked effectively
at high altitude.
Even if workers have been shown to tolerate these

Figure 29.2 Enormous diesel electric truck at the

modern Collahuasi mine in north Chile. This can
transport 240 tons of copper ore.

340 Commercial activities at altitude

Table 29.2 Increase in mine equipment size at 3000 m
and 4000 m to achieve the same output as at sea level

Diesel engines
Compressors
Vacuum filters
Vacuum pumps
Transmission lines
Transformers
Electrical machines
Flotation
Leach vessels

Brake horsepower
Airtool work
Tons solids rr1
Intake volume
MVA km-1
MVA
kW
tons h-1
tons h-1

40
55
30
30
20
15
15
35
50

55
75
45
40
30
25
25
50
85

Source: modified from Jimenez (1995).

high altitudes reasonably well, it should not be

expected that they can accomplish the same amount
of physical work as at sea level. The decline in maximal oxygen consumption with increasing altitude
was discussed in Chapter 11, where it was pointed
out that the Vo 2max of an acclimatized subject at an
altitude of 5000 m is only about 70 per cent of the sea
level value. Another way of looking at this is that the
work force would have to be increased by about
40 per cent at high altitude to accomplish the same
amount of physical work. It is interesting that this
inefficiency is not confined to human beings, but is
also seen in mechanical equipment. Table 29.2 shows
that, at an altitude of 4000 m, the amount of equipment to produce the same amount of work as at sea
level has to be increased from 25 to 85 per cent
(Jimenez 1995).
29.4
29.4.1

TELESCOPES
Mauna Kea

As indicated previously, there have been mines at

altitudes over 4000 m in the South American Andes
for many years, even before the Spanish invasion.
However, the practice of siting telescopes at high altitude is much more recent, mostly within the last
50 years. There are several advantages in siting telescopes at high altitudes. One is that the instrument is
then above much of the Earth's atmosphere, which
otherwise absorbs some of the optical and radio
waves. Another advantage is that in some areas, for

example Chajnantor (see below), the atmosphere is

extremely dry and absorption of radio waves by
water vapor is therefore much less. Finally, remote
mountain sites tend to have little light or radio wave
pollution, although this advantage can also be
achieved in other remote areas at lower altitudes.
Two telescope sites will be considered here. One is
the extinct volcano at Mauna Kea in the big island of
Hawaii. The summit is at an altitude of 4200 m and
at least 10 instruments are located either on the summit or not far below it. A feature of Mauna Kea is that
it is close to the city of Hilo, which is at sea level, and
it is possible to drive from one site to the other in a
couple of hours. There is also an intermediate station
with dormitories at 3000 m at Hale Pohaku, and
some newcomers can spend a night there before
going to the summit. However, the majority of the
staff who operate the telescopes commute from sea
level every day. The barometric pressure at the summit is about 465 mm Hg, so the P02 of moist inspired
gas is only 87 mm Hg, as against 150 mm Hg at sea
level. The hypoxic stress is therefore severe.
Forster (1986) has studied the incidence of acute
mountain sickness (AMS) and the arterial blood
gases of some of the workers on the United Kingdom
Infrared Telescope (UKIRT) on the summit of
Mauna Kea. These shift workers spent 40 days working at sea level at Hilo, followed by a 5-day shift at
high altitude. The first night of the shift was spent in
the dormitories at 3000 m, and following that 4 days
were spent on the summit of Mauna Kea, with the
workers returning to 3000 m for each night. It was
found that 80 per cent of the shift workers had
symptoms of AMS on their first day at the summit.
Apart from breathlessness, headache was the most
frequent complaint, and this affected 41 per cent of
shift workers at the start of their high altitude shift.
Other common symptoms were insomnia, lethargy,
poor concentration, poor memory, and unsteadiness
of gait. The frequency of symptoms decreased over
the 5 days of the shift, and at the end 60 per cent of
the workers were asymptomatic.
Arterial blood gases were measured in 27 UKIRT
shift workers. On day 1 at 4200 m, the mean arterial
P02 was 42 mm Hg, rising to 44 mm Hg on day 5. The
arterial PC02 was 29 mm Hg on the first day, falling to
27 mm Hg on the fifth day. Arterial pH was 7.49 on
day 1, falling to 7.48 on day 5.
It is interesting that there was no difference in the
incidence of AMS between shift workers who worked

Oxygen enrichment of room air 341

at the summit after a brief sojourn at sea level (mean

4 days), compared to a protracted rest period (mean
37 days) at sea level. This suggests that in this group,
the acclimatization to high altitude achieved during
5 days on Mauna Kea was lost within a few days of
return to sea level. High altitude pulmonary edema
(HAPE) was rarely seen at Mauna Kea, with only 1
case in 41 shift workers during a 2-year study period.
Also only one worker on Mauna Kea had an episode
of high altitude cerebral edema (HACE).

29.4.2

Chajnantor

The other telescope site that will be discussed here is

Chajnantor in north Chile, southeast of San Pedro de
Atacama, at a latitude of 23S and an altitude of
5000 m. This is a remarkable site because it is fairly
flat, covers a large area, and is easily accessible by
road from San Pedro (altitude 2440 m). The first part
of the road is an international highway leading from
Chile to Bolivia and Argentina, and the final 15 km is
now also paved. The drive from San Pedro to
Chajnantor takes only about 1 h. There must be few
places in the world where it is possible to reach an
altitude of 5000 m so easily.
Several small radio telescopes have been sited at
Chajnantor or nearby. At the time of writing, the
California Institute of Technology has a radio telescope that is studying the cosmic microwave background radiation. However, part of the interest of
Chajnantor is that it will be the site of an enormous
multinational radio telescope, construction of which
will start in 2004. When finished it will be the largest
radio telescope in the world, with a cost of $400 million. Since the barometric pressure is 420 mmHg,
the inspired P02 is only 78 mm Hg, so the degree of
hypoxic stress is substantial. The large amount of
construction work required to complete the telescope, and the number of workers who will be at the
site to run it, means that this is a particularly challenging problem in high altitude medicine.

29.5
OXYGEN ENRICHMENT OF ROOM
AIR TO RELIEVE THE HYPOXIA OF HIGH
ALTITUDE

work has recently been done on the feasibility and

value of raising the oxygen concentration of room air
at high altitude in order to relieve the hypoxia. The
possibility of doing this was suggested by Cudaback
(1984) and, at one stage, plans were made to oxygen
enrich the control room of the Keck telescope at
Mauna Kea, although these never materialized.
The principle of oxygen enrichment is simple.
Oxygen, either from a concentrator or a cryogenic
source, is added to the ventilation of a room, thus
increasing the oxygen concentration from 21 per
cent to a higher value. The reason why oxygen
enrichment is so powerful is that relatively small
degrees of oxygen enrichment result in large reductions of equivalent altitude. The term 'equivalent
altitude' refers to the altitude at which the moist
inspired P02, when a subject is breathing ambient air,
is the same as the inspired P02 in the oxygen-enriched
environment. Figure 29.3 shows that, between altitudes of 3000 and 6000 m, each 1 per cent of oxygen
enrichment results in a reduction of equivalent altitude by about 300 m. In other words, if we oxygen
enrich a room at the Chajnantor site, altitude
5000 m, by 6 per cent (that is, we increase the oxygen
concentration from 21 to 27 per cent), the equivalent
altitude is reduced by about 6 x 300 m, or 1800 m.
Therefore we go from an altitude of 5000 m to one of
3200 m, which is much more easily tolerated.

Figure 29.3 Degree of reduction of equivalent altitude (meters of

descent per 1 per cent oxygen enrichment) plotted against the
altitude at which the enrichment is made. Note that at altitudes

Partly in response to the burgeoning of commercial

and scientific activities at high altitude, considerable

up to about 6000 m, each 1 percent of oxygen enrichment results

in an altitude reduction of more than 300 m. (From West 1995.)

342 Commercial activities at altitude

When this idea was originally proposed, some

people argued that it would be impossible to maintain an enriched-oxygen atmosphere within the
room because of inevitable leaks. However, in practice, oxygen enrichment is relatively simple and reliable. The room does not have to be gas tight. Large
potential leaks such as window surrounds are taped,
and a double door is provided so that there is an air
lock. However, oxygen-enriched air is blown into the
room and escapes through small leaks, and in practice it is easy to control the oxygen level within
0.25 per cent.
Oxygen enrichment of rooms has become feasible
largely because large quantities of oxygen can now be
produced relatively cheaply. The simplest way to do
this is to use an oxygen concentrator; thousands of
these are now used in homes to provide oxygen for
patients with chronic lung disease. The principle is
that air is pumped at high pressure through a nonflammable ceramic material such as synthetic zeolite
which absorbs nitrogen from the air. The result is
that the effluent gas has a high oxygen concentration,
typically 90-95 per cent. After 20-30 s, the zeolite is
unable to absorb more nitrogen and the compressed
air is then switched to another cylinder containing
the same material. The original cylinder is then
purged of nitrogen by blowing air through it at normal pressures. In this way, a continuous supply of
90-95 per cent oxygen is available. A typical unit
provides 5 L min"1 of nearly pure oxygen at a power
consumption of 350 W. It is also possible to provide
the oxygen from liquid oxygen tanks, but this is more
expensive and less convenient because the tanks need
to be replenished.
An important issue is what level of ventilation to
use in the room. Clearly, the higher the ventilation,
the larger the amount of oxygen that must be
produced to maintain a given degree of oxygen
enrichment. This topic has been discussed extensively elsewhere (West 1995). We use the 1975
American Society of Heating, Refrigeration and
Air-Conditioning Engineers (ASHRAE) standard
of 8.5m3 person-1 h-1, which corresponds to
142 L min'1. This is calculated to maintain the carbon
dioxide concentration in the room below 0.24 per
cent, based on a carbon dioxide production rate per
person of 0.3 L mirr1. This concentration of carbon
dioxide was chosen by ASHRAE as a measure of
acceptable ventilation levels. Substantially higher
concentrations of carbon dioxide can exist without

people being aware of them. However, the carbon

dioxide concentration is a useful objective marker of
adequacy of ventilation, and higher levels tend to be
associated with awareness of body odor.
It should be added that in 1989, ASHRAE
increased the minimum standard of ventilation by
three to fourfold. This was a somewhat controversial
decision, and was partially based on the facts that
there may be smokers in the room, there are health
variations among people, and some types of room
furniture cause outgassing, which may be injurious.
In designing a facility for use at high altitude, it can
be assumed that people will not be allowed to smoke
in the room, and it is also possible to choose furniture that does not provide outgassing hazards.
Figure 29.4 shows a sketch of a module that can be
used for oxygen enrichment in the field. In this
instance, a standard shipping container of dimensions 20 ft (6.1 m) long, 8 ft (2.44 m) wide and 8 ft
high is fitted out as a living space with beds, or a laboratory or a machine shop. A larger laboratory can be
housed in a standard shipping container of dimensions 40 ft (12.19 m) long by 8 ft wide by 8 ft high.
Such containers are currently in use at the
Chajnantor site, in connection with the CalTech
radio telescope. The oxygen is provided from oxygen
concentrators, and the concentrations of both
oxygen and carbon dioxide are continually monitored inside the rooms.
The experience of the astronomers with oxygen
enrichment has been very satisfactory. There have
been no technical problems in maintaining the target
oxygen concentration of 27 per cent, and the carbon
dioxide concentration is typically less than 0.25 per
cent. The CalTech project was a particularly valuable
field test of oxygen enrichment because, for the first
2 weeks, the astronomers were working in ambient
air conditions. They found this extremely tiring,
despite the fact that they slept every night at San
Pedro (altitude 2440 m). When the oxygen enrichment modules were set up, they noticed an immediate improvement in work productivity and
efficiency. In fact, they soon instituted a rule that no
one was allowed to control the telescope or use
power tools unless using oxygen enrichment. When
the astronomers were not in the oxygen-enriched
modules, they used portable oxygen in order to provide oxygen enrichment. They also reported that it
was feasible to sleep at the Chajnantor site in the
oxygen-enriched rooms. This had not proved to be

Oxygen enrichment of room air 343

possible while breathing ambient air because of the

poor quality of sleep.
Several studies have now been carried out on the
physiological effects of oxygen enrichment of room
air at high altitude. The first studies were performed
at the Barcroft facility of the White Mountain
Research Station (altitude 3800 m) in California,
where the oxygen concentration of the test room was
raised from 21 to 24 per cent (Luks et al. 1998). This
reduced the equivalent altitude to about 2900 m. In a
double- blind study, it was shown that oxygen enrichment during the night resulted in fewer apneas and
less time spent in periodic breathing with apneas.
Subjective assessments of sleep quality showed significant improvement. There was also a lower AMS
score during the morning after oxygen-enriched

sleep. An unexpected finding was that there was a

larger increase in arterial oxygen saturation from
evening to morning after oxygen-enriched sleep than
after sleeping in ambient air (Figure 29.5). Of course,
both measurements of arterial oxygen saturation
were made with the subject breathing ambient air.
In another study, the mechanism of the unexpected increase in arterial oxygen saturation the
following morning was investigated (McElroy et al.
2000). Because this could have been caused by a
change in the control of ventilation, the ventilatory
responses to hypoxia and to carbon dioxide were
measured in the evening and in the morning after
sleeping both in the oxygen-enriched environment
and in ambient air. No effect of oxygen enrichment
on the control of ventilation was found. An

Figure 29.4 A self-contained oxygen-enriched module suitable for field work at high altitude. The module uses a standard shipping
container 20 ft (6.10 m) long and 8ft (2.44 m) wide and high. These oxygen-enriched modules are being used at the California Institute of
Technology radio telescope at Chajnantor, altitude 5050 m.

344 Commercial activities at altitude

Figure 29.5 Change in arterial oxygen saturation from evening to

morning for subjects sleeping in ambient air, compared with the
same subjects sleeping in 24 per cent oxygen enrichment, at an
altitude of 3800 m. The measurements of oxygen saturation were
made by pulse oximetry, with the subjects breathing ambient air.
The increase was greater after sleep in oxygen enrichment
(p < 0.05). (From Luks et a I., 2000.)

alternative explanation is that the increase in arterial

oxygen saturation seen following sleep in the
oxygen-enriched environment might have been the
result of less subclinical pulmonary edema, compared with sleeping in ambient air. An interesting
additional piece of information that might support
this explanation was that the increase in arterial oxygen saturation was transient, so that by midday the
difference between the oxygen-enriched and ambient air treatments on oxygen saturation was abolished.
A final study was carried out on the effects of oxygen enrichment on neuropsychological function at a
simulated altitude of 5000 m, as referred to briefly in
Chapter 16. Again, the Barcroft facility, at an altitude
of 3800 m, was used, and the concentration of

oxygen in the room was manipulated to simulate

ambient air at an altitude of 5000 m, and an oxygen
concentration of 27 per cent at an altitude of 5000 m.
A large battery of neuropsychological tests was performed in a double-blinded manner, and it was
found that there were significant improvements in
reaction times, hand-eye coordination, and mood
(Gerard et al. 2000). These findings are directly relevant to the project of oxygen enrichment at the
Chajnantor site.
An important consideration when oxygen is added
to air is whether the fire hazard is increased, compared with sea level. This has been analyzed carefully
(West 1997) and it has been shown that, with the levels of oxygen enrichment considered here, the fire
hazard is less than at sea level. The basic reason is
that, although the P02 is increased by oxygen enrichment at high altitude, it is still far below the value at
sea level. Although it is true that the reduction of PN2
at altitude also increases the fire hazard to a small
extent, because of the smaller extinguishing effect of
this inert gas, it remains true that the fire hazard
using the degrees of oxygen enrichment described
here is less than at sea level. As an example, the
National Fire Protection Association (NFPA 1993)
defines an oxygen-enriched atmosphere as having an
increased fire hazard, in the sense that it will support
an increased burning rate of materials, if the percentage concentration of oxygen is greater than
23.45/(Pf)0.5, where Pf is the total barometric pressure
expressed as a fraction of the sea level pressure. For
the Chajnantor site, Pf = 0.55, so that if the oxygen
concentration is greater than 31.6 per cent it would
exceed the NFPA threshold. The oxygen concentration of 27 per cent is well below this value.
It could be argued that oxygen enrichment of
room air represents a new attitude to living and
working at high altitude. Until now, most people
have accepted hypoxia as something that has to be
endured. However, this proactive attitude of raising
oxygen concentration of the rooms to reduce the
equivalent altitude could represent a major advance.

30
Athletes and altitude
30.1
30.2
30.3
30.4
30.5
30.6

Introduction
Altitude and training
The mountaineer as an athlete
Polycythemia and increased hematocrit
Detraining and hypoxia
Living high-training low

345
346
346
347
347
348

SUMMARY
It is only recently that athletes have used high altitude training to enhance sea level performance, but
many remarkable feats of endurance have been
recorded in mountains. One of the most remarkable
was the first ascent of Everest without supplementary
oxygen in 1978.
In athletic competitions at altitude, slower times
are recorded in sprint events because of lowered air
resistance, whilst in endurance events, because of a
lower Vo2max, times are slower.
The paradox is that acclimatization to altitude
results in central and peripheral adaptation that
enhances oxygen delivery and utilization, but
hypoxia decreases the intensity of training and may
even cause detraining.
As polycythemia increases the V02max and endurance
performance, this might indicate that the higher the
athlete goes to train the better, but this is not the case;
an increased hematocrit carries its own disadvantages,
as well as the problem of decreased exercise capacity
resulting in decreased training intensity.
There is some evidence that athletes who live at
moderate altitude (2500 m) and train at low altitude
(1500 m) improve their endurance performance.
However, there is considerable individual variation
in the results of the 'live high-train low' method,

30.7
30.8

Critical P02 for hematological adaptation

Measurement of the effects of altitude
training
30.9 Immune response at altitude
30.10 Is altitude training worth it?

348
348
348
349

and in one series, sea level V02max did not improve,

yet race times improved by about 6 per cent.
For maximal sea level performance it is still not
clear how long or how high the athletes should live at
altitude or how long they should remain at sea level
before racing.
Unfortunately, few trials have adequate sea level
controls to compare with altitude training. Until this
is done much information will remain largely anecdotal.

30.1

INTRODUCTION

Pugh (1965) suggested that athlete performance at

altitude would result in slower times in sprint events
due to decreased air resistance, which parallels barometric pressure; by contrast, in distance events times
would be increased because the maximum oxygen
uptake falls with altitude.
Comparing the times of athletes in the 1965 PanAmerican games held in Mexico (2250 m) with those
of the Melbourne Olympics of 1956 at sea level, Pugh
showed that there was an increase in time of
2.6 per cent in the 800 m and 14.9 per cent in the
10 000 m events. In the 100 m and 400 m, but not the
200 m, race times at altitude were faster than at sea
level.

346 Athletes and altitude

When the Olympic Games were held in Mexico

City in 1968, several world records in short and
sprint events were broken but in the longer
endurance events times were slower than at sea level.
This was due to the reduced V02 max which at this altitude is 84 per cent of sea level values. However, the
times were not as slow as had been predicted.
Marathon performance at altitude is affected
mainly by a lowered V02max, which decreases by
about 1.5-3.5 per cent for every 300 m of ascent
above 1500 m (Roi et al 1999).
30.2

ALTITUDE AND TRAINING

To achieve optimum physical performance at altitude it is clear that adequate acclimatization to

hypoxia is essential or, better still, being bom and
bred at altitude. Evidence that after a period at altitude returning to sea level improves performance is
still equivocal and the timing for maximum sea level
performance after altitude training is not clear.
However, altitude training is frequently used by
competition athletes to improve their sea level performance, despite lack of evidence that it is beneficial. On the one hand acclimatization to high altitude
results in central and peripheral adaptations that
improve oxygen delivery and utilization. Hypoxic
exercise may increase the stimulus of training thus
magnifying the effect of endurance training. On the
other hand, the hypoxia of altitude limits the intensity of training and may result in detraining.
Numerous anecdotal reports suggest that
endurance athletes benefit from altitude training;
however, when appropriate controls have been
included in studies, the benefit has been found to be
no greater than equivalent training at sea level. Many
results are equivocal. Using controls Roskamm et al.
(1969) found that subjects who trained at 2250 m
improved their V02max by comparison with sea level
subjects and those at 3450 m, but Hanson et al.
(1967), also with sea level controls and starting with
unfit subjects, (Vo 2 max < 40 mL mkr-1 kg-1), found no
advantage in training at an altitude of 4300 m. In well
trained subjects too, the picture is not clear. A well
controlled study by Adams etal. (1975) using a crossover design in experienced trained athletes (V"02max
73 mL mhr-1 kg -1 ) showed no significant differences
in performance between altitude (2300 m) and sea
level training.

It is not clear which physiological parameters are

important. Altitude training may result in a greater
density of muscle capillaries, but this can also be
achieved by training at low altitude. In addition,
hypoxia over a long period in lowlanders causes loss
of muscle mass and increased capillary density due
mainly to a decrease in muscle fiber density. In any
event lowland athletes, using altitude training, cannot in a few weeks or months achieve the effect of
lifetime exposure.
Some of the best endurance runners have been
born and bred in East Africa, living at an altitude of
1500-2000 m, and this upbringing will contribute to
their continued success. Also, hypoxia increases
hemoglobin concentration which is associated with
an increased endurance performance. However,
Weston et al. (1999) have compared elite African
10 km runners and their white counterparts, both of
whom lived at sea level. The African runners had a
greater resistance to fatigue, and higher oxidative
enzyme activity, combined with a lower accumulation of lactate.
With the difference between winning and losing
an event being often so small, the psychological
effects of altitude training should not be discounted.

303
THE MOUNTAINEER AS AN
ATHLETE
The first mountaineers who could be called
athletes were Hebler and Messner (Messner 1979,
pp. 178-82). In 1978, they made the first ascent of
Everest without supplementary oxygen and this
focused attention on their birth, upbringing and
training at intermediate altitude in the European
Alps. A number of high altitude natives have
repeated this feat on Everest, but then so have mountaineers born and bred at sea level (Unsworth 2000).
Habler and Messner's training, which included
long distance running and very rapid alpine ascents
up to 4875 m and later rapid ascents in the
Himalayas, played a major role in their exceptional
fitness and subsequent success.
With training, outstanding feats of endurance
have been recorded. In 1899, a Ghurka soldier born
and bred at intermediate altitude in Nepal ascended
and descended a 800 m peak in Scotland and crossed
4 miles of scree and bog in 55 min. This feat was

Detraining and hypoxia 347

repeated in 1999 by a trained athlete (a fell runner) in

53 min 45 s (The Times 1999b).
Other outstanding endurance feats at low and high
altitude are recorded. For instance, a man in his
fiftieth year ran 391 miles in 7 days 1 h 25 min over
Lakeland hills up to 850 m in the UK. This involved a
total ascent of 37 000 m, an average of over 5000 m
per day (Brasher 1986). In June 1988, 76 summits in
the same region were reached in 24 h involving an
ascent and descent of 12 000 m (Brasher 1988). At
intermediate altitude all 54 of the peaks over 4300 m
in Colorado, USA, were climbed in 21 days (Boyer
1978) and the ascent of Mont Blanc (4807 m) in
France from Chamonix (1050 m), with return to
Chamonix, was made in 5.5 h (Smyth 1988). At high
altitude, one ascent in the Karakoram Mountains was
made from 4900 m to 8047 m with return to 4900 m
in 22 h (Wielicki 1985) and on Mount McKinley in
Alaska from 3000 m to 6000 m in 19 h (Rowell 1982).
In 1986 an ascent and descent of Everest (8848 m)
in 2 days by a new route on the north face was completed from the head of the West Rongbuck glacier
(5800 m); supplementary oxygen was not used (Everest
1987). In 1990, MarcBatard ascended from Base Camp
to the summit of Everest in 22.5 h also without the use
of supplementary oxygen (Gillman 1993, p. 200).

30.4
POLYCYTHEMIA AND INCREASED
HEMATOCRIT
Up to about 2500 m polycythemia increases the
^o2max and endurance performance (Levine and
Stray-Gundersen 1992). For this reason the use of
erythropoietin by subcutaneous injection or autologous blood transfusion, both of which create a transient increase in red cell mass, has been banned for
athletic events. The effect of autologous red cell infusion on exercise performance at high altitude
(4300 m) was studied by Pandolf et al. (1998). No
significant improvement in a 3.2 km run at sea level
was found after infusion, and at altitude times were
only slightly faster.
Hypoxia stimulates the release of erythropoietin
and in turn the bone marrow is stimulated to produce more red cells. The process takes weeks rather
than days, however, and the initial rise in hemoglobin and hematocrit on going to altitude is almost
entirely due to a reduction in plasma volume

(Chapter 8). The increase in hematocrit is advantageous as it increases the oxygen-carrying capacity
of the blood. However, the resulting reduction in
blood volume may be part of the reason for the
reduction in cardiac output found at an early stage of
altitude exposure. For the sea level athletes training
at altitude, this decrease in plasma volume on ascent
is rapidly reversed on descent and any advantage in
terms of hematocrit is quickly lost. In a person resident at altitude for many months or years, the red
cell mass may be increased by as much as 50 per cent
of its normal sea level value. On descent to sea level
this increased cell mass is retained for some weeks
which could be an advantage in endurance events.
It is still not clear what the optimum altitude is at
which athletes should be taken to maximize their
performance.
Considering the inverse relationship between P02
and hemoglobin concentration, it might be thought
that the higher the athlete can go the better, but
recent work (Gore et al. 1998) suggests that altitude
training at 2650 m does not increase V02max or
hemoglobin. Also when sea level dwellers spend long
periods over 5000 m physical and mental deterioration occurs, associated with loss of appetite, loss of
weight and reduction of muscle mass (Ward 1954).
In addition a high hematocrit carries with it the danger of transient or permanent vascular episodes and
possible death.

30.5

DETRAINING AND HYPOXIA

It has recently been seen that in elite endurance athletes, Vo2max can be reduced at altitudes as low as
610 m (Gore et al 1996). This occurred in about
50 per cent of trained subjects with V02max above
65 mL min-1 kg-1 (Anselme et al. 1992), and they
appeared to develop a more severe level of arterial
hypoxemia during maximal and submaximal exercise than more sedentary controls under hypoxic and
normoxic conditions (Lawler et al. 1988, Koistenen
etal. 1995).
This might have been due to a detraining effect
(Saltin 1967). However, it has also been suggested
that intermittent exposure to altitudes of
2300-3300 m maximizes the balance between
acclimatization and intensity of training (Daniels
and Oldridge 1970). It is also possible that the inten-

348 Athletes and altitude

sity of training at sea level could produce as good a

result as intermittent visits to altitude.

30.6

LIVING HIGH - TRAINING LOW

Levine and Stray-Gundersen (1997) suggested that if

athletes were acclimatized to a moderate altitude
(2500 m) and trained at lower altitude (1500 m) they
could get the best of both worlds and improve their
performance more than an equivalent control group
at sea level or altitude. A 5000 m run time trial was
the main measure of performance and in trained
runners those who 'lived high - trained low' showed
an increase in sea level performance. Sea level performance was not improved in those who lived and
trained at moderate altitude or in those who lived
and trained at sea level only.
There is, however, considerable individual variation in the response to altitude training and some do
not respond to the 'live high - train low' regime
(Chapman et al 1998).

30.7
CRITICAL P02
n, FOR HEMATOLOGICAL
ADAPTATION
In one study of elite cross-country skiers, 3 weeks'
training at an altitude of 1900 m was sufficient to
raise the hematocrit by 5 per cent (Ingier and Myhre
1992). However, the scarcity of similar studies does
not allow any definite conclusion to be made.
It has been suggested that the longer the period at
altitude the greater the hemopoietic response.
However, during the Silver Hut Expedition 1960-1,
when 3 months were spent at 5800 m and above, the
hemoglobin concentration leveled off after about
6 weeks.
Obviously hypoxia increases the demand for iron
and athletes training at altitude may prove to be iron
deficient, particularly female athletes. Again few
studies have been made but differences in iron status
may explain differences in individual hematological
response (Ingier and Myhre 1992).
On descent from altitude hemoglobin levels return
to normal quite quickly. In Operation Everest III
(COMEX) after 30 days in a chamber ascending to
the equivalent height of the summit of Everest, the
hemoglobin concentration was back to normal val-

ues after 4 days at sea level pressure (Richalet et al.

1999). Also after a long period at altitude individuals
feel physically 'slack' and less energetic for the first
few days. Most coaches therefore advise return to low
altitude at least 2-3 days before an important race.

30.8
MEASUREMENT OF THE EFFECTS
OF ALTITUDE TRAINING
Because so many hypoxic training studies have been
completed without normoxic controls, it is difficult
to determine whether the physiological changes
noted are due to hypoxia alone or a training effect.
In one series with controls, 10 elite middle to long
distance runners trained for 10 weeks at the same
exercise rate at sea level and at a simulated altitude of
4000 m. There was no improvement in Vo2max> vet
personal best times over 10 km improved by about
6 per cent (Asano et al. 1986). Is it possible that this
was due to a psychological effect?
Anaerobic performance may also improve after
returning to sea level, following a stay at altitude, but
many studies have shown no improvement (Martin
and Pyne 1998).

30.9

IMMUNE RESPONSE AT ALTITUDE

The question of immunity and training even at sea

level is a hotly debated subject as is immunity and
altitude. However, the possibility that training at altitude may cause some defect in the immune system is
real. A defect in B cell function has been suggested
but not proved (Meehan 1987). On Operation
Everest II when individuals ascended to the 'summit'
of Everest in a decompression chamber, results suggested that T-cell activation was blunted during
exposure to severe hypoxia whereas B-cell function
and mucosal immunity were not (Meehan et al.
1988).
Athletes frequently complain of recurrent minor
infections, and mountaineers at high altitude find
that cuts and infections seem to improve more
rapidly on return to lower altitude. Bailey et al.
(1998), in two studies with a total of 24 elite
endurance athletes training at altitudes of
1500-2000 m, found a 50 per cent increase in the
frequency of upper respiratory and gastrointestinal

Is altitude training worth it? 349

tract infections during the altitude period. They also

recorded a reduction in plasma glutamine concentration at rest. Glutamine is important as a substrate for macrophages and lymphocytes and a
reduction in its concentration might indicate
impairment of immune defense against opportunistic infections.
30.10

IS ALTITUDE TRAINING WORTH IT?

Is it worthwhile for athletes to train at altitude? At

present there is no clear answer to this question. The
disadvantages are the risk of AMS and HAPE and
RACE. The reduction of V02max and the earlier onset
of fatigue mean that altitude training is less intense
than at sea level. However, living high and training
low has shown improved performance in a 5 km time
trial.

On the strength of that one trial, it would seem

that for distance events it would be better to live at
2500 m and train at 1500 m. Bailey and Davis (1997)
reviewed the available evidence for the efficacy of
altitude training for sea level events and concluded,
Scientific evidence to support the claim that either
continuous or intermittent hypoxic training will
enhance sea level performance remains at present
equivocal.

The optimum time of stay at altitude is still not

clear, but to increase red cell mass at least 4 weeks at
altitude may be necessary, but the associated reduction in training intensity would not be advantageous.
To obtain maximum performance after the athlete
descends to lower levels, the timing of the event is
also not clear: a minimum of 2-3 days with a maximum of 14-21 days has been suggested (Suslov
1994).

31
Clinical lessons from high altitude
31.1

Introduction

350

31.6

Chronic anemia

355

31.2

Chronic obstructive lung disease

31.7

Interstitial lung disease

Cyanotic heart disease
Low output cardiac conditions

Hemoglobinopathies with altered oxygen

affinity

355

31.3
31.4
31.5

351
353
354
354

31.8

Contribution of high altitude physiology to

clinical medicine

355

SUMMARY
The study of healthy subjects at altitude has given
valuable insights into the effects of hypoxia on
human physiology. In this chapter we consider the
similarities and differences between humans at high
altitude and patients at sea level with various medical
conditions. Altitude acclimatized humans are a very
good model for the hypoxia suffered by patients with
lung diffusion limitation due to conditions such as
fibrosing alveolitis and pneumoconiosis where there
is little or no airways obstruction. Chronic obstructive lung diseases (chronic bronchitis, emphysema
and chronic asthma) have many similarities to acclimatized humans but differ in that such patients have
normal or raised PC02 whereas acclimatized humans
have a low PCOr Healthy subjects at altitude have
some similarities to patients with cardiac conditions
which limit the heart in its response to exercise. The
sensation of fatigue in the working muscles is similar
and is experienced by both. It is probably due to
insufficient oxygen supply in both cases. Anemia
gives rise to the same sensation due to oxygen lack
though through different mechanisms. The problems of patients with cyanotic heart disease are also
reflected in acclimatized humans.
At a more fundamental level altitude physiology has
influenced clinical medicine through concepts such as

the importance of partial pressure of gases, especially

of oxygen and carbon dioxide and, by extension, of
anesthetic gases, and of acid-base and oxygen dissociation curves. Much early work was stimulated by
interest in humans and animals at altitude. In hematology the very early work on polycythemia of altitude
provided a stimulus to much work on erythropoiesis.
In cardiology the raised pulmonary artery pressure
found at altitude has stimulated work on the control
of pressure in the lesser circulation.

31.1

INTRODUCTION

High altitude medicine and physiology constitute a

legitimate subject for study in their own right and if,
like any branch of science, such study casts light on
other fields, including clinical medicine, that is a
bonus.
However, it is often argued that a justification for
human studies at high altitude is that the knowledge
so gained may be applied in clinical medicine.
Patients hypoxic because of pulmonary or cardiovascular disease present a complex picture in which
hypoxia is only one of their many problems. In the
study of humans at high altitude one can study the
effects of hypoxia alone in otherwise healthy subjects.
The stimulus, hypoxia, can be applied in a measur-

Chronic obstructive lung disease 351

able controlled way at a time to suit the scientist, so

that controlled measurements can be made before
and after hypoxia.
The insight so gained can be applied to the more
complicated uncontrolled situation of the hypoxic
patient. This chapter discusses how good a model
human subjects at high altitude are for the hypoxic
patient, and the similarities and the differences
between these two situations. It also reviews the
extent to which high altitude physiology has illuminated clinical medicine.

31.2
CHRONIC OBSTRUCTIVE LUNG
DISEASE
Probably the commonest cause of hypoxia in medicine is chronic obstructive lung disease (COLD).
Within this category are included patients with
chronic obstructive bronchitis, emphysema and
chronic fixed asthma. Patients with long-standing
severe deformity, such as kyphoscoliosis, also develop
hypoxia in the later stages of their disease. Table 31.1
lists the similarities and differences between a patient
with COLD and a subject at high altitude.
31*2.1

Symptoms

The similarities include the symptoms of dyspnea,

especially on exertion, and the limitation of work

capacity. Dyspnea is a difficult sensation to describe

and probably the term includes more than one sort of
sensation. Patients with asthma, for instance, say that
the sensation during an attack is quite different from
the breathlessness they feel at the end of a run when
free of asthma. The dyspnea of an individual at high
altitude is probably more like the latter; the sensation
is of needing to hyperventilate and being quite free to
do so. Patients with COLD, on the other hand, probably suffer a rather different sensation, akin to that of
the asthmatic patient in an attack, which is described
as a difficulty in 'getting the breath' or of suffocation.
The reduction in work or exercise capacity is very
similar in both patients and high altitude subjects. In
both, the dyspnea is felt to play a part but both also
complain that work is limited by a sensation of the
legs 'giving out' or 'feeling like lead'. This is for large
muscle mass dynamic work such as walking, cycling,
and climbing stairs. If the strength of a small muscle
mass is tested (e.g. hand grip), it is found to be largely
unimpaired in both cases. The possibility that the
central nervous system may play a role in limiting
exhaustive exercise fatigue at altitude has been proposed (Kayser et al 1993b). Could this also apply to
patients with COLD?
In the patient with COLD the work of breathing
(per liter) is increased because of airways obstruction. The total ventilation may be increased as well,
even if there is alveolar hypoventilation, because of
the increased dead space; thus the total work of
breathing is further increased. At high altitude, the

Table 31.1 Comparison of clinical aspects of chronic obstructive lung disease with findings in people at high altitude

Dyspnea on exertion
Limited work capacity
Peripheral edema
Polycythemia
Red cell mass
Arterial P02
Arterial PC02
Arterial pH
Bicarbonate level in blood, CSF
Work of breathing L-1
Work of breathing, total
C02 ventilatory response
Cerebral blood flow
Pulmonary arterial pressure
CSF, cerebrospinal fluid; AMS, acute mountain sickness.

Yes
Yes

Yes
Yes

Seen in AMS

Frequent

Yes

Yes

Increased
Reduced
Reduced
Raised
Reduced
Reduced
Increased
Shift to left and steepened
Increased/normal
Raised

Increased
Reduced
Normal or raised
Normal or reduced
Raised
Increased
Increased
Shift to right and flattened
Increased
Raised

352 Clinical lessons from high altitude

work of breathing per liter is modestly decreased

because of the reduction in air density at reduced
barometric pressure; however, the total work of
breathing is increased due to the marked hyperventilation especially on exercise (Chapter 11).

31.2.2 Blood gases and acid-base

balance
Subjects at high altitude and patients with COLD
both have reduced P0r At high altitude this is due to
low inspired P02 whereas in COLD patients it is
caused by gas transfer problems due to
ventilation/perfusion ratio inequalities. In both
cases, the hypoxemia is made worse by exertion.
The PC02 level, however, is different. In patients
with COLD the -Pac02 is either normal or, in more
severe cases, raised. The pH is consequently lowered;
respiratory acidosis and secondary renal compensation result in elevated blood bicarbonate concentration. The cerebrospinal fluid (CSF) bicarbonate
concentration is also elevated and there follows a
shift to the right of the ventilatory carbon dioxide
response line and the response becomes flattened
(i.e. blunted). In contrast, at high altitude the Pac02 is
reduced, pH elevated, blood and CSF bicarbonate
concentration reduced, and the carbon dioxide
response shifts to the left and becomes more brisk
(Chapter 5).

31.2.3

Hematological changes

At high altitude and in COLD patients there is an

increase in red cell mass. This invariably results in
polycythemia at high altitude where it is accompanied at first by a reduced plasma volume (Chapter 8).
In COLD the plasma volume is usually increased, for
reasons which are unclear, so that polycythemia is
often not seen until red cell mass is considerably
increased by a more extreme hypoxia. In both cases
the increase is due to more erythropoiesis, stimulated
by increased levels of erythropoietin. After the first
few days at a given high altitude, levels of erythropoietin fall to within the normal or control range
(Chapter 8) and similarly, in over half the patients
with polycythemia due to hypoxic lung disease,
erythropoietin levels are within the normal range
(Wedzicha et al. 1985).

Plasma volume, as already mentioned, is increased

in COLD. Plasma volume is decreased on first going
to altitude but returns towards normal after about
3 months (Chapter 8). In high altitude residents
plasma volume is decreased by about 27 per cent compared with sea level residents (Sanchez et al. 1970).

31.2.4
edema

Fluid balance and peripheral

Patients with COLD are at risk of developing peripheral edema, mainly dependent, and raised venous
pressure. They have been shown to have a defect of
sodium and water handling; they fail to excrete a
water load at the normal rate if they have a high PC02
(Farber et al. 1975, Stewart et al. 1991a). COLD
patients have a reduced effective renal plasma flow
and urinary sodium excretion. They may have raised
plasma renin activity and aldosterone levels. The
development of peripheral edema may take place
without increase in body weight (Campbell et al.
1975), suggesting a transfer of fluid from intracellular to extracellular compartments. This is in contrast
to edema formation in cardiac failure when, as
expected, it is associated with weight gain. How these
findings can be fitted into a coherent account of the
mechanism of this condition is still not clear.
The fluid balance in people at high altitude is also
far from clear. It seems likely that the development of
acute mountain sickness (AMS) is associated with
fluid retention, whereas the healthy response on
going to high altitude is a diuresis. Peripheral edema
frequently occurs in AMS, often affecting the periorbital regions and hands as well as the ankles,
whereas pulmonary edema and cerebral edema are
the malignant forms of AMS (Chapters 18-20). In
the acclimatized there is no evidence of any problem
in fluid handling.
Whether there are analogies between the mechanisms of AMS and cor pulmonale are questions for
future research in both fields. For instance, it is the
COLD patients with high -Pac02 who are likely to
develop cor pulmonale, and in subjects at altitude
higher Pac02 may be associated with AMS.

31.2.5

The circulation

The systemic circulation is not importantly affected

by either COLD or altitude. There is often mild

Interstitial lung disease 353

elevation of the blood pressure in both cases, but

there are important changes in the pulmonary circulation. In both patients with COLD and those at high
altitude there is increased pulmonary resistance,
resulting in raised pulmonary artery and right ventricular pressures and similar electrocardiographic
(EGG) changes (i.e. right axis deviation) (Chapter 7).

that absorption of both o-xylose and 3-o-methyl-Dglucose was reduced in subjects at 6300 m, and
Travis et al. (1993) also found a reduction in the ratio
of these carbohydrates at 5400 m, indicating impairment of absorption (Chapter 14).

31.2.6

Patients with hypoxia due to COLD frequently have

disturbance of mental function, especially during
exacerbations, when their P02 falls to very low levels.
In the milder stages these disturbances may be quite
subtle but, as hypoxia becomes severe, patients
become irritable, restless and confused. Motor function may become impaired with ataxia. These
changes are very similar to those observed in healthy
subjects exposed to acute hypoxia in decompression
chambers. However, in acclimatized subjects, very
low saturations may be seen, especially on exercise,
with very little mental disturbance, though at
extreme altitude and with AMS these mental problems maybe seen (Chapter 16).

Cerebral blood flow (CBF)

In patients with COLD the CBF is increased due to

the cerebral vasodilatory effects of both hypoxia and
hypercarbia. On going to altitude the CBF is normally modestly increased at first, then tends to fall
towards sea level values (Severinghaus et al. 1966b).
This is due to the low Pac02, which tends to reduce
CBF opposing the effect of hypoxia. Polycythemia, as
it develops in both COLD patients and those at high
altitude, will tend to reduce CBF. Very low CBF values have been inferred from the large arteriovenous
cerebral oxygen difference in Andean altitude residents with marked polycythemia (Milledge and
Sorensen 1972) whereas patients with COLD are to a
degree protected from cerebral hypoxia by their
hypercapnia, which causes increased CBF.

31.2.7

Alimentary system

There has been little work on the effect of hypoxia on

bowel function in either patients or individuals at
high altitude. Milledge (1972) showed that small
bowel absorption, as measured by the xylose absorption test, was reduced in patients with either hypoxic
lung disease or cyanotic heart disease, when the saturation fell below about 70 per cent. It was suggested
that this finding might explain the loss of weight
which often characterizes patients with severe
emphysema towards the end of the course of their
disease.
Subjects at high altitude tend to lose weight and,
although much of this weight reduction is due to
reduced energy intake, there has been uncontrolled
evidence that at altitudes above about 5500 m there is
continued weight loss even with adequate energy
intake (Pugh 1962a). During the American Medical
Research Expedition to Everest (AMREE) in 1981,
there was a significant reduction in both fat and
xylose absorption in subjects at 6300 m (Blume
1984). More recently Dinmore et al. (1994) found

31.2.8

31.2.9

Mental effects

Summary

Table 31.1 summarizes the similarities and differences between patients with COLD and those at high
altitude. Healthy people at altitude differ in a number of important respects from patients with hypoxia
due to COLD. Most of these differences are attributable to the one being hypocapnic and the other
hypercapnic. However, the hypoxia is, of course,
similar and results in similar effects on a number of
bodily systems, including erythropoiesis, muscles,
the alimentary system and mental function.
Providing the carbon dioxide effect is borne in mind,
persons at high altitude can be considered as a model
for the hypoxia of COLD.

31.3

INTERSTITIAL LUNG DISEASE

Within this category are included such conditions as

sarcoidosis, fibrosing alveolitis, allergic alveolitis
(farmer's lung, etc.), pneumoconiosis (including silicosis) and other causes of diffuse pulmonary fibrosis. Some types of pneumonia, for instance that due
to Pneumocystispneumoniae, which are diffuse rather

354 Clinical lessons from high altitude

than lobar, present similar pathophysiology. In all

these conditions the main problem is an impairment
of gas exchange. There usually develops some restriction of lung volumes as well but, unlike COLD, there
is little or no airways obstruction. The result is that
hypoxia develops without any rise in Pacc,2. Indeed,
the Pac02 is characteristically decreased as it is in subjects at high altitude.
The dominant symptom in these patients is
breathlessness on exertion and, later, even at rest.
The arterial desaturation becomes worse on exertion
just as it does in those at extreme altitudes (Chapter
12). The cause of the hypoxemia in these patients is a
defect of gas transfer. This is due to ventilation/perfusion ratio inhomogeneity and an increase in the
diffusion path length, that is, a thickening of the
alveolar capillary membrane by cellular infiltrate or
fibrosis. In most cases the ventilation/perfusion mismatch problem is the more important. These conditions usually develop over a period of months and a
subject well acclimatized to high altitude is a very
good model for the hypoxia of a patient with interstitial lung disease.

31.4

CYANOTIC HEART DISEASE

Most patients in this group have congenital cardiac

defects which result in right to left shunts and therefore in cyanosis. Diagnoses include tetralogy of
Fallot, ventricular and atrial septal defects with
reversed shunts, patent ductus arteriosus with
reversed shunt, and most forms of anomalous
venous drainage.
These patients, often hypoxic from birth, sometimes have most extreme cyanosis with severe polycythemia. -Pac02 is usually in the normal range but
may be low as is found at high altitude. Those with
extreme polycythemia, in whom the hematocrit can
be up to 70 per cent, resemble cases of chronic mountain sickness and may suffer the same symptoms of
lethargy, poor concentration, being easily fatigued,
etc. (Chapter 21). Though they do get out of breath
on exertion, dyspnea is not a prominent symptom,
perhaps because the condition has been present since
birth. Again, like chronic mountain sickness and the
'blue bloater' type of COLD patient, it may be due to
a blunted respiratory drive. The histopathology of the
pulmonary circulation of children with cyanotic heart

disease is comparable to that of high altitude residents

(Heath and Williams 1995 pp. 121-39). The normal
demuscularization of pulmonary arteries after birth
is retarded so that the wall thickness, especially of the
resistance arterioles, is increased compared with the
normal pulmonary arterial tree (Chapter 17).
Children with cyanotic heart disease have retarded
growth, as do children at altitude (Chapter 17). If
their defect can be corrected by surgery, growth accelerates and they catch up with their peers. If their arterial saturation is below about 70 per cent they will
have impaired small bowel absorption which may
contribute to their growth retardation. Surgical repair
of the defect relieves the cyanosis and the small bowel
absorption improves (Milledge 1972). In this respect
they resemble those at high altitude (Chapter 14).

31.5
LOW OUTPUT CARDIAC
CONDITIONS
Ischemic heart disease and cardiomyopathy can
result in low cardiac output. In milder forms of this
condition the output at rest is normal but there is
failure of the normal response to exercise of an
increase in cardiac output. Patients are symptom free
at rest but find that their exercise tolerance is
markedly diminished; they can only walk slowly and
the slightest uphill slope causes them to stop and rest.
They are not limited by dyspnea but by fatigue in the
leg muscles. In these patients the Pa02 is normal, but
blood flow is limited, which reduces oxygen delivery
and results in tissue hypoxia. The tissues most
affected are those which have a high extraction of
oxygen and which increase their oxygen demand on
exercise, that is, the working muscles. The mixed
venous Pa02 is very low but Pac02 is normal.
The subject at high altitude is obviously not such a
good model for this type of patient, but, especially at
extreme altitude, there are physiological similarities.
The maximum cardiac rate and output are limited to
some degree (Chapter 12), so that, during large
muscle mass dynamic exercise, oxygen delivery to the
working muscles is limited. There is certainly tissue
hypoxia, especially of these muscles, due to a reduction in delivery of oxygen and possibly also to limitation of oxygen diffusion at the tissue level (Chapter
12). As mentioned in section 31.2.1, the sensation of
work being limited by 'the legs giving out' rather

Contribution of high altitude physiology to clinical medicine 355

than dyspnea alone is common both to individuals at

high altitude and to these patients.

31.6

CHRONIC AN EM IA

Patients with chronic anemia have a very similar

pathophysiology to patients with low cardiac output.
The oxygen delivery to the tissues is reduced in their
case by the reduced oxygen capacity of the blood.
Cardiac output increases, partly due to a decreased
viscosity of the blood, and this partially compensates
for the loss of oxygen-carrying capacity. Nevertheless,
oxygen delivery is reduced, especially to the working
muscles, during exercise. The resulting symptoms are
similar to those of low cardiac output and have their
analogy in those at extreme altitude.

jects with Hb Andrews-Minneapolis, a high affinity

hemoglobin (P50 =17 mm Hg), found that they had
less reduction in exercise capacity on going to altitude than their siblings with normal hemoglobin.
Normal subjects at high altitude, especially at
extreme altitudes above 8000 m, have their oxygen
dissociation curves shifted to the left by respiratory
alkalosis; this is probably advantageous for the above
reason (Chapters 9 and 11). Thus, those at high altitude can be a model for some aspects of hemoglobinopathies.

31.8
CONTRIBUTION OF HIGH
ALTITUDE PHYSIOLOGY TO CLINICAL
MEDICINE

31.8.1
31.7
HEMOGLOBINOPATHIES WITH
ALTERED OXYGEN AFFINITY
The hemoglobinopathies are a rare, but interesting,
group of conditions in which patients have a genetic
defect resulting in minor changes to their hemoglobin. These changes result in their hemoglobin having either a greater or a reduced affinity for oxygen
compared with normal hemoglobin. The oxygen dissociation curve is shifted either to the left (increased
affinity) or to the right (decreased affinity).
Patients with increased affinity hemoglobin experience a degree of tissue hypoxia because oxygen is not
readily unloaded in the tissues. This evidently stimulates erythropoietin production since these patients
are typically polycythemic.
Conversely, patients with decreased affinity hemoglobin are anemic, presumably because their tissue
P02 is higher than normal, as evidenced by the ease
with which oxygen is unloaded there. At moderate
altitude this may confer some advantage, though this
has not been demonstrated, and on exercise the difficulty of oxygen loading in the lungs would probably
outweigh any advantage in the tissues. At higher altitude the difficulty in loading oxygen into the blood
in the lungs would certainly be a disadvantage.
Indeed, increased oxygen affinity is probably
beneficial, since, at high altitude, the advantage in the
lungs more than outweighs the disadvantage in the
tissues. A study by Hebbel et al. (1978) of two sub-

Partial pressure of gases

The importance to clinical medicine of Paul Bert's

work published in his landmark La Pression
Barometrique (1878) is enormous. This work clearly
showed that it is the partial pressure of oxygen,
rather than the barometric pressure or oxygen percentage, that determines the effect of hypoxia in
causing mountain sickness and death. Although he
did not work at altitude himself he corresponded
with and encouraged people who did, and used
chambers to reduce the ambient pressure for both
human and animal subjects. He can truly be claimed
as a father figure for both altitude physiology and
aviation medicine. Of course, other physiologists and
clinicians after Paul Bert developed the idea of the
partial pressure of gases and its importance, including such workers as Haldane, Douglas, FitzGerald,
Henderson, Schneider, Bohr, Krogh and Barcroft, all
of whose work was stimulated by the problems of
altitude physiology.
The concept of the effect of gases on the body
being due to their partial pressures (especially of oxygen and carbon dioxide) is fundamental to respiratory medicine and physiology, and to aviation and
underwater medicine. In anesthesia the partial pressure of gases extends to all volatile agents.

31.8.2

Hematology

The polycythemia of high altitude was first documented by Viault (1890) and has been extensively

356 Clinical lessons from high altitude

studied ever since. As a tool in hematological

research, this stimulus to erythropoiesis has been
invaluable. Much of the early work on the oxygen
dissociation curve, by Haldane, Barcroft and others,
owes its stimulus to the question of human survival
and acclimatization to high altitude. These 'lessons
from high altitude' are amongst the foundation
stones of modern hematology, open heart surgery,
respiratory medicine, cardiology and anesthetics.
More recently, research on 2,3-diphosphoglycerate
and its influence on the position of the oxygen
dissociation curve has been studied at altitude
(Chapter 9) and the results incorporated into the
body of hematological knowledge.

31.83

Respiratory medicine

Work on the effect of altitude acclimatization on the

control of breathing (Chapter 5) has helped in the
understanding of the changes in control of breathing
in patients with COLD with hypercapnia. These
patients 'acclimatize' to a high Pac02 and their carbon
dioxide ventilatory response becomes blunted, the
opposite of altitude acclimatization. They are then
dependent on hypoxia as a drive to ventilation and
may have their breathing depressed if given high
inspired oxygen mixtures to breathe.
In patients with asthma, as the condition worsens,
their Pa02 falls. At first the Pac02 is reduced because of
the hypoxic drive to ventilation; then, with increasing
airways resistance, Pac02 rises to 'normal' and finally
rises above normal. Cochrane et al. (1980) have
pointed out that the Pac02ln the middle of these three
stages should be below 'normal', depending on the
degree of hypoxia. Drawing on altitude data, Wolff
(1980) gives a predicted value for Pac02, dependent
on Pa02 The patient should be considered to be in
respiratory failure if the Pac02is above this value. For
instance, a patient with a Pa02 of 60 mm Hg has a

predicted Pacc,2 of 30 mm Hg, assuming full acclimatization to this degree of hypoxia.

Study of the increasing arterial desaturation due to
diffusion limitations found in climbers on exercise at
altitude (Chapter 6) helps in the understanding of
the similar problems in patients at sea level with
interstitial lung disease and limited diffusing
capacity.

31.8*4

Cardiology

The phenomenon of the hypoxic pulmonary pressor

response has been studied at sea level and altitude in
humans and animals, with results from altitude stimulating work at sea level and vice versa. The insights
gained have helped in the understanding of patients
with pulmonary hypertension due to hypoxia secondary to heart or lung disease.

31.8.5

Other areas of clinical medicine

High altitude physiology and medicine have lessons

for other branches of clinical medicine, for example:
small bowel function, which is impaired at altitude as well as in hypoxic patients (Chapter 14)
metabolism, in the slower growth of children at
altitude, and patients hypoxic due to congenital
heart disease
reproductive medicine, in the problem of fertility
at altitude
endocrinology, in the effect of hypoxia on various
endocrine systems (Chapter 15), and their counterparts in patients with similar conditions.
However, these fields have been less thoroughly
explored both by high altitude and by clinical scientists. No doubt high altitude has yet more lessons to
teach clinical medicine in the future.

32
Practicalities of field studies
32.1
32.2
32.3
32.4
32.5

Introduction
Laboratory work in the field
Respiratory measurements
Cardiological measurements
Sleep studies

357
360
361
362

32.6
32.7
32.8
32.9

Blood sampling and storage

Hematology
Computers
Other areas of scientific study

363
364
364
364

362

SUMMARY
The practical difficulties of carrying out good
research at altitude in the mountains are obvious and
are considered in this chapter. However, there are
many compensations. The difficulties can be met by
careful planning and by choosing projects and techniques that are appropriate for field work.
The advantages and disadvantage of field versus
chamber studies, including cost, are discussed. There
is a place for both types of study and they are complementary. Most of the techniques of classical
cardiorespiratory and exercise physiology have been
used at altitude. Blood urine and saliva samples can
be taken, stored and brought back for biochemical
and hormonal analysis. With the advance of electronics quite sophisticated techniques in sleep studies, audiometry, visual fields, psychometric testing
and even Doppler echocardiography and nearinfrared spectroscopy have been used in the field.
Laptop computers have been used at great altitudes
and can be used on line with the more sophisticated
equipment.
In planning either a pure scientific expedition or
one in which science is combined with mountaineering, it is important to ensure the support of all members for the scientific program. This is best done by

communicating the objectives of the program to

everyone in simple terms and giving all members
(professional and lay) an active role in the science.

32.1

INTRODUCTION

The problems associated with field research in the

great ranges are obvious and include cold, hypoxia,
fatigue and lack of amenities of civilization such as
piped hot and cold water, reliable electricity supplies,
heating, etc. The lack of easy access to specialist
advice from service engineers or colleagues can be a
severe problem. However, there are compensations.
Perhaps the greatest is the elimination of distractions
from the work in hand. There is no commuting to
work, no committees, no lectures to give or attend,
no family commitments and little in the way of social
events. If the site has been well chosen there is the
added advantage of living for a while among the
grandest and most beautiful scenery on Earth.

32*1.1

Planning, testing and practice

Many of the data referred to in this book have been

collected on expeditions to the major mountain

358 Practicalities of field studies

regions of the world. Good scientific work under

these conditions can be difficult but is perfectly possible, providing adequate time, thought and effort
are given to planning and preparation. The preparation time will be at least 3-6 months for a small
expedition and 2 years or more for a major scientific
expedition.
The techniques and apparatus to be used must be
tested adequately beforehand. Many studies require
control measurements at sea level and these are best
carried out using the same equipment as will be used
in the field. Not only are results more reliable if the
same equipment is used, but problems and deficiencies are identified before leaving for the mountains.
Practice with the equipment in the comfort of a standard laboratory is also highly desirable, though not
absolutely essential. One of the authors of this book
taught one of the others the technique of gas analysis
using the Lloyd-Haldane apparatus during the
course of their first Himalayan expedition at 5800 m.
Even if study protocols do not demand control
measurements before leaving, it is advisable to carry
out a complete dummy run of the observations to be
made, listing all the equipment needed, down to the
last rubber band and needle.

32.1.2

Field versus chamber studies

Although this chapter is concerned with field studies

at altitude, much valuable work has been done in
decompression chambers. The advantages of chamber studies over field studies are:
Rate of ascent and descent, and altitude can be
controlled to suit the problem under study.
Other factors such as temperature and humidity
can be controlled.
More invasive procedures can be justified since, in
the event of some complication, help is readily
available.
The disadvantages are perhaps not so obvious,
especially to people who have not been involved
with such work. Living for more than a few hours
in a decompression chamber is not pleasant. The
environment is usually noisy, confined and often
smelly - though this is less true of large modern
facilities such as the chamber at Natick, MA, operated by the US Army Institute of Environmental
Medicine. However, even the largest chamber is

cramped compared with being in the mountains

and it is difficult and very boring to take much
exercise. Acclimatization seems to be slower and
less complete in chamber studies than on the
mountain. Values for Pcc,2 are consistently higher
for the same altitude in chambers than on the
mountain. This may be due to less exercise taken by
subjects in chambers or due to other factors or
stresses (Rahn and Otis 1949, Houston 1988-9,
West 1988b). In studies lasting more than a few
hours, boredom, and hence morale, is a problem. A
limiting factor for chamber studies is the number of
subjects that can be accommodated. This might be
less of a drawback for most physiological studies
but it would be important in studies of acute
mountain sickness (AMS) where a large number of
subjects is needed to ensure that some have symptoms and others are unaffected. Finally, chambers
are built with specific tasks in mind; usually their
use is geared to short-term experiments on acute
hypoxia and so they may not be available to altitude
scientists for prolonged experiments.
In comparing the results of studies carried out in
the field with those done in low pressure chambers, it
is useful to look at the results obtained from the
Silver Hut Expedition and the American Medical
Research Expedition to Everest (AMREE), and compare these with the two major simulation studies to
date, Operation Everest I and II. In many areas, the
results of the two types of studies have been very similar. For example, the measurements of maximal
oxygen consumption for the inspired P02 on the
summit of Mount Everest were almost identical in
AMREE and Operation Everest II. However, the two
types of studies have yielded quantitatively different
information in some areas, presumably because of
the different periods of acclimatization. The main
differences are seen in three areas:
Alveolar gas composition. The shorter period of
acclimatization in the two low pressure chamber
studies to date resulted in very different alveolar
P02 and PC02 values at extreme altitudes compared
with the results from the field studies (see Figure
12.4). The differences are particularly marked for
Operation Everest I and are discussed in section
12.3.3.
Blood lactate concentration. Blood lactate concentrations after maximal exercise were appreciably higher on Operation Everest II than on

Introduction 359

the AMREE and extensive field measurements

made by Cerretelli (1980). These are shown in
Figure 12.5 and discussed in section 12.3.4.
Again the differences are presumably due to the
shorter period of acclimatization on Operation
Everest II. This topic is discussed fully by West
(1993b).
Exercise ventilation at extreme altitude. As was
pointed out in section 11.3, both the Silver Hut
Expedition and AMREE found a decrease in
ventilation at maximal exercise at extreme altitude (see Figure 11.3). By contrast, maximal
exercise ventilation on Operation Everest II continued to increase with greater altitude. The
reason for the differences is not clear; it is
presumably related to the different degrees of
acclimatization.

32.13

Cost

It is often assumed that chamber studies must be

cheaper than field studies. This is not necessarily the
case. Accounting in both cases is a very inexact science. The cost of a mountaineering expedition is
clear, but in many cases the climbers are going to the
mountains anyway and the scientific work can be
carried out at very little extra cost. Chambers represent a huge capital cost but usually the altitude scientist is not called upon to contribute to this. However,
even the running costs of a chamber are not inconsiderable. Apart from the subjects and scientists,
chambers have to manned 24 h a day by teams of
highly trained technicians whose salaries have to be
met. If all expenses are charged realistically to the
study, long-term chamber projects are very expensive.
In summary, chambers are very useful in studies of
acute and subacute hypoxia lasting a few hours.
Their advantage over field studies becomes less as the
duration of the study and the number of subjects
increase. Thus the two modes of research are complementary.

32.1.4

Personnel management

The psychodynamics of a mountaineering expedition are fascinating and of vital importance in

achieving both climbing and scientific goals, but too
great an emphasis on psychological factors may well

be self-defeating. The essential aspect of leadership of

a scientific expedition is to ensure that the whole
team is as fully aware of the scientific program as
possible and in sympathy with it. Climbers may be
suspicious of scientists but can understand quite
abstruse scientific argument providing terms and
concepts are explained in everyday language. They
are naturally interested in topics such as AMS, work
performance at altitude and the effect of altitude on
various biological systems and can become enthusiastic participants, providing the issues are clearly
explained.
Time spent in presenting the scientific program
to the whole team is well spent, as was evident
from experience on the AMREE, where climbers as
well as climbing scientists were enthusiastic about
working on the scientific program as well as climbing the mountain. In a large party with a number
of scientists it is equally important that the various
scientific members understand the relevance of
each other's projects and are in sympathy with
them.
After presenting the program, the next essential is
to delegate responsibility as widely as possible. It is
highly desirable that every member of the expedition
has a job to do in relation to the scientific program,
for two reasons.
The programs are usually overambitious in terms
of what can be achieved in the time available and,
by sharing the work out, the load on the main
scientists is reduced.
By having a designated job, each member feels he
or she is personally committed to the scientific
program, with consequent improvement in
morale. This is particularly important if nonscientific members are expected to act as subjects.
Having a job to do as well as being a subject avoids
the feeling, 'they only want me as a guinea-pig'.
There are many jobs which can be carried out
perfectly well by expedition members who are not
scientifically trained, such as measurement of
urine volume or body weights, or clerking results
as another member reads them off. Even the spinning and pipetting of blood samples can be
quickly taught. A further important aspect of delegating work as widely as possible is that it helps
to keep the work going should any of the scientific
members be unable to function owing to illness or
accident.

360 Practicalities of field studies

32.2
32.2.1

LABORATORY WORK IN THE FIELD

Laboratory accommodation

However small the expedition, some form of designated laboratory accommodation is recommended.
For small expeditions this will be a tent; if at all possible it should be of the type high enough to stand up
in, and have a folding table and chairs. Cold is a
major problem in the mountains. Most types of
scientific work cannot be carried out in temperatures
below 5-10C, and certainly not below freezing.
Battery operated instruments work poorly below
freezing, plastic bags crack easily and venepuncture is
difficult because of vasoconstriction. Under severe
freezing conditions blood samples will freeze and
hemolyse. If there is no space heating available, the
time for scientific work will be limited to the warmest
hours of the day. However, it must also be said that at
high altitude the sun is strong and when it is shining
on a tent the temperature rises rapidly inside, even
though the outside shade temperature remains well
below zero. On the recent Medical Research
Expeditions to Kangchenjunga no less than five large
tents, each 3 m x 5 m floor area, were set up at Base
Camp (5100 m) in which up to 12 teams successfully
worked on over 20 projects. There was also a large
dome tent which was used for a mess tent, communications, battery and power control facility.
On a large expedition, good laboratory conditions
can be achieved by using a modern 'tent', such as a
Weatherport (Hansen Weatherport, Gunniston,
CO). This is a tubular aluminium frame with padded
plastic cover made in various sizes which proved very
satisfactory in the Western Cwm in 1981 (West
1985a). Heating was provided by a propane stove of
the type designed for mobile homes in which a heat
exchanger heats the air, which is blown into the tent.
In this way there is no possibility of carbon monoxide from the burning propane entering the tent.
Carbon monoxide poisoning is a real danger from
less sophisticated forms of heating.
The Silver Hut similarly provided almost ideal
conditions in 1960-1, though at far greater expense.
It was a prefabricated hut made from boxed-up
marine plywood members with foam insulation
within the box sections. A similar hut but using fiberglass sections was used at Base Camp on the AMREE
and was also successful. Work surfaces, seating and

lighting should also be provided. In such conditions,

the working day can be prolonged into the night if
necessary, allowing more work to be carried out than
in an unheated laboratory, as well as avoiding the
problem of cold as an interfering factor if one is
studying the effects of chronic hypoxia.

32.2.2

Electrical supply

Early in the planning of an expedition the decision

will have to be made about whether to use mains
voltage apparatus or to restrict work to battery operated and nonelectrical equipment.
The advantages of mains voltage equipment are
obvious, and certain types of equipment are only
available as mains operated versions. It is possible to
get petrol-powered generators that weigh not more
than one porter load, and on a large expedition this is
the chosen option. The disadvantages are not inconsiderable. In order to try to ensure that one generator
is working, at least two must be taken; even then it is
quite likely that both will break down. Extra spare
parts must be taken and at least one expedition
member should be a mechanic with knowledge of
that particular generator. Altitude affects petrol
engines as it does the animal organism and adjustments must be made to the fuel mix, usually by
changing the jets in the carburetor. Some generators
are available with variable jets, in which case the settings required for various altitudes should be ascertained before the expedition. The power output
declines with altitude, as it does in humans, so a
more powerful generator must be taken than would
be needed for the same equipment at sea level. Petrol
and oil must also be carried.
Alternative sources of electrical power have been
used. In the Silver Hut Expedition much of the electricity used over the winter was derived from a wind
generator and on the AMREE a battery of solar cells
gave almost 30 A at 15 V. In both cases this power
was fed into 12V storage batteries and mains voltage
was obtained by using converters. These introduced
their own degree of inefficiency, as well as further
expense and transport penalties. In 1998 on
Kangchenjunga we were able to supply almost all our
not inconsiderable power needs from solar cells
because we were fortunate with the weather.
However, this required discipline in the use of power
especially in the morning to allow the batteries to

Respiratory measurements

charge up in the morning sun after they had been

used at night often for communication by satellite
phone. These alternative sources cannot be relied
upon and petrol generators are needed for back up.

32.23

Water, reagents, etc.

Water at altitude is obtained either from melting

snow or ice or from mountain streams. In either case
it has a fairly high degree of purity so that for most
chemical uses it will be adequate if water is passed
through a deionizing column which will include a filter. If distilled water is essential it will have to be carried out from home.
Analytical balances are impractical in the field.
Reagents should be weighed at the home institution
into capped tubes. These can then be made up in the
field as needed by dissolving in deionized water.

323
323.1

RESPIRATORY MEASUREMENTS
Classical methods

Classical measurements of ventilation and oxygen

consumption using Douglas bags, taps and valves are
as easy to carry out in the field as in the laboratory
(providing all the bits are remembered, including the
nose clip). The gas meter will be of the dry type or a
Wright's respirometer (anemometer) can be used if
care is taken not to empty the Douglas bag too fast
through it (accuracy 2 per cent). The gas analysis is
more of a problem for the physiologist used to using
a mass spectrometer. If mains voltage is available
(section 32.2.2) an infrared carbon dioxide meter
and paramagnetic oxygen meter can be used, though
calibrating gases will have to be carried.
Paramagnetic oxygen analyzers are available as battery operated instruments but carbon dioxide meters
are not. Alternatively, one can be really classical and
use the Lloyd-Haldane or Scholander apparatus and
analyze samples chemically.
Care should be taken with modern Douglas bags.
The plastic that is used now for these bags is much
less likely to become hard and brittle in the cold than
was previously the case but care may be needed if
overnight temperatures have been very low. A repair
kit should be taken.

323.2

361

Alveolar gas sampling

Alveolar or end-tidal gas samples have been taken

from subjects at altitude on a number of expeditions,
in 1981 from the summit of Everest itself.
Glass ampoules were successfully used on a
number of expeditions, including the Silver Hut
Expedition, when samples were brought back from
7830 m. These were of 50 ml capacity and had a stem
with two necks in it. The ampoules were pre-evacuated before leaving. In the field, a Haldane-Priestley
sample was delivered down a tube with the ampoule
attached to a side arm by a short length of pressure
tubing. Surgical forceps were then used to break the
glass within the pressure tube and the sample entered
the ampoule. With the rubber tube clamped the
ampoule was brought back to base where, with a suitable gas flame, the ampoule was sealed at the lower
neck and transported back for analysis.
More recently, 20 ml aerosol cans of the type used
in asthma inhalers have been successfully used. These
cans, supplied by the pharmaceutical industry, had
the metering device removed and were then preevacuated. They were shown to hold their vacuum
for at least 6 months. In the field, the simplest apparatus involved merely a T-shaped piece of tubing into
the stem of which the can was fitted with its nozzle
resting on a shoulder. The subject delivered a
Haldane-Priestley alveolar sample across the T to
which was added a soft, widebore tube; the can was
then depressed, which opened its valve, and the
sample entered the can. Releasing the can sealed it
again and it was then transported back for analysis.
The actual device used on the summit of Everest
was rather more complicated (West 1985a); it held
six pre-evacuated cans in a rotating cylinder to which
two handles were attached. The subject blew across
the top of the cylinder through two one-way valves
and the end-tidal gas was caught between them. On
squeezing the handles, one can was opened and a
sample taken. On releasing the handles the can was
closed; the cylinder rotated to present the next can
for a second sample (Maret etal 1984).
Analysis at the home institute was by mass
spectrometry using a special inlet device which
would accept the aerosol can. The sample volume at
sea level pressure would be only 5-7 mL.
If rapid carbon dioxide and oxygen analyzers are
taken, end-tidal gases can be measured over sufficient time to be sure of a steady state.

362 Practicalities of field studies

3233 The Oxylog and electronic

spirometers
The Oxylog is a portable electronic instrument giving
a continuous read-out of minute ventilation and oxygen consumption (updated each minute), and the
total ventilation and oxygen consumption since it was
last reset. The subject wears a mask, into the inspiratory port of which is fitted an electronic spirometer or
anemometer. It is normally supplied with rechargeable batteries but can be modified to take nonrechargeable batteries. The output (V and V02) can be
recorded for hours on a portable tape recorder. It is
accurate for submaximal work rates (Milledge et al.
1983c) but is not suitable for V02max measurements.
Ventilation alone can be recorded using one of a
number of electronic spirometers such as that used
in the Oxylog, though the resistance of most commercially available models is not well tolerated at the
very high ventilation found in climbers exercising at
altitude. Such an electronic spirometer was successfully used by Pizzo near the summit of Everest (West
etal 1983c).

323.4

Pulse oximetry

The pulse oximeter allows the easy measurement of

arterial oxygen saturation with a very lightweight
battery powered instrument. There are many models
on the market now and most are accurate and reliable. They also read heart rate. Many also have data
storage facilities and data can be downloaded into
laptop computers. This allows them to be readily
used for sleep studies. They are not suitable for
ambulatory measurements, though they can be used
during exercise on a cycle ergometer. The sensors are
made for use either on the finger or earlobe, the former being usually preferred. It is essential for the finger to be warm in order to get a good signal.

32.4
32.4.1

CARDIOLOGICAL MEASUREMENTS
Electrocardiography (ECG)

The ECG is easy to record at altitude, either the classical 12-lead ECG at rest, or ambulatory recording
over many hours. Such recordings have been made
on Everest climbers (West et al. 1983c). The pulse

rate can be obtained from such recordings.

Computer analysis can be carried out looking for
arrhythmia and spectral analysis of R-R intervals, etc.
Care is needed in the electrode placement and
attachment (as at sea level).

32.4.2

Echocardiography

Until recently the size, weight and complexity of

ultrasound machines for conducting echocardiography were such that there was no question of using
this technique in the field. However, machines are
getting smaller, lighter and more reliable and it can
now be considered as a possibility. Such a machine
was used by Dubowitz at the Himalayan Rescue
Association Clinic at Pheriche (4243 m) to complete
a study measuring pulmonary artery pressure by
Doppler echocardiography in trekkers on their way
to Everest Base Camp (Dubowitz and Peacock 1999).
The same machine was taken to Kangchenjunga Base
Camp (5100 m) but unfortunately developed a fatal
electrical fault soon after the study started.

32.43

Cardiac catheterization

More invasive cardiac techniques, such as right heart

and pulmonary artery catheterization, have been discussed and, though possible under field conditions
with mains voltage electricity available, are probably
not justified, though this is debatable. Catheterization has been carried out in chamber studies, most
extensively in Operation Everest II (Houston et al.
1987); in skilled hands it carries very little risk.

32.5

SLEEP STUDIES

Sleep studies have been carried out on a number of

expeditions where mains voltage was provided
(Chapter 13). ECGs, electroencephalograms (EEGs),
electro-oculograms, ear and pulse oximetry and respiratory movements have all been monitored simultaneously and recorded on tape and paper while the
subject was asleep. Most of this monitoring can be
carried out with battery operated instruments but it
is important that some way of monitoring the signals
during the recording is provided, even if the analysis
from tape is left until after the expedition.

Blood sampling and storage 363

32.6
32.6.1

BLOOD SAMPLING AND STORAGE

Venepuncture

There is little problem in performing venepuncture in

the field. Two physician climbers took samples from
each other on the South Col of Everest the morning
after climbing to the summit (Winslow et al. 1984).
'Vacutainer' systems using pre-evacuated tubes and
double-ended needles are particularly convenient, as
the sampling tubes are used for centrifuging. They fill
(from the vein) perfectly well at altitude.

32.6.2

Centrifuging blood samples

If mains voltage is available, a small electrical centrifuge can be used and this presents no problem. Hand
centrifuges can be used but require quite a lot of
muscle power. They need to be spun very vigorously
for 15-20 min; even then the cells are not as tightly
packed as by even the lowest powered electrical centrifuge. This means that the yield of plasma is less,
typically a maximum of 5 ml from 10 mL of blood.
When subjects become polycythemic the problem
becomes worse.
These hand centrifuges usually take four 10 mL
tubes compared with six or eight in the small electrical centrifuges; they are really intended for spinning
urine samples and are not designed for such vigorous
spinning. Older designs with brass gears and cast
metal casings stand up better than do modern models with nylon gears and plastic cases. A firm bench on
which to clamp the centrifuge is essential. However,
with all these drawbacks, hand centrifuging of blood
is possible if mains voltage is unavailable. A dry battery centrifuge is not a viable possibility.

32.6.3 Arterial blood sampling and

analysis
If the usual precautions are taken and if the doctor is
experienced in the procedure, there should be no
problem in arterial puncture. Arterial cannulation is
more hazardous and probably not justified in the
field. The measurement of arterial pH, P co2 and PO2 is
really not possible without mains voltage for the
various meters and temperature control. Although

there is no inherent reason why these electrodes

could not be run from battery operated electronics,
the market is not big enough for manufacturers to
develop them commercially.

32.6.4

Sample storage

Plasma, serum and urine samples can be deep frozen,

stored and transported back to the home laboratory
by using liquid nitrogen in a suitable container. In
previous editions of this book we described how a
portable deep-freeze container could be made by
using a 28 L liquid nitrogen flask (often called a
Dewar flask) and packing it with dry ice (solid
carbon dioxide). This gave up to 130 days of use.
However, dry ice is no longer readily obtainable so
this method has now been abandoned. There was
also the disadvantage that although the necks of these
flasks were quite narrow, they could not be tightly
sealed because the nitrogen could not evolve and
there would be danger of explosion. Therefore there
was always the potential for spillage of liquid nitrogen and harm to porters, though I know of no such
accident ever happening.
However, systems have now been developed for
the safe transport of deep-frozen samples using liquid nitrogen trapped in an absorbent matrix inside a
vacuum container. One such commercial system is
called a Cryopak. Much of the capacity of the flask is
taken up with the filler material and there is quite a
small well for the samples. The makers supply a vial
holder or canister, which slides into this well and
takes sample vials. This allows vials to be removed,
inspected, sampled and replaced but further reduces
the capacity of the flask. Alternatively the canister
can be dispensed with and vials just thrown into the
well. This allows more samples, but at the risk of losing labels, and makes sorting more of a problem.
There is a range of flask sizes with capacity ranging
from 30 to 324 2 mL vials. The gross weight when
charged with nitrogen ranges from 7.3 to 22.7 kg.
The static holding time (full of liquid nitrogen) is
30 days but the working time (absorbed nitrogen
only, empty well) is only 21 days. The flask, of course,
can be topped up with liquid nitrogen. This system is
safer than the previous one since once any excess liquid nitrogen has evolved, there is no risk of spillage.
This means that they can be freighted on aircraft as
normal instead of going as 'dangerous goods' and, of

364 Practicalities of field studies

course, they are safer as porter loads. This system was

used on the recent Kangchenjunga Expedition. The
more limited time available is a disadvantage and
without the benefit of helicopter freight and topping
up we would have had difficulty in keeping our samples frozen until return to London.
Samples should be taken into PTFE tubes with
good screw caps. Tubes should have a matt surface
for labeling, which should be done in pencil; they
should then be covered in low temperature adhesive
tape. During transportation (if the canister or
holder is dispensed with) these tubes are constantly
chafed together, and unless the labels are firm they
will come off or run and all will be lost. It was found
that pencil under low temperature clear adhesive
tape was safe.
For shorter periods of up to 1-2 weeks, it may be
adequate to use polystyrene boxes of dry ice.
Although the newer Cryopak flasks are not treated
as 'dangerous goods', airline regulations are
frequently changed and anyone planning to use
these or other systems should check the current
regulations with the airline they are using, including the container requirements in force. Airlines
are usually familiar with handling 'medical samples'
in this way but expect to deal with recognized
shippers. The bureaucracy and expense of such a
shipment are not inconsiderable; delays of a few
days at each end can be anticipated and must be
allowed for in calculating the time available at
deep-freeze temperature.

32.7

HEMATOLOGY

Much hematology can be done with quite simple

equipment in the field. Battery operated microcentrifuges for packed cell volume are available
commercially. Hemoglobin can be measured by the
cyanmethemoglobin method and a battery operated
spectrometer. Cell count can be carried out by classical microscopy techniques. With mains voltage
electricity and P0a electrodes, the oxygen dissociation curve and P50 can be measured (Winslow et al.
1984).

32.8

COMPUTERS

Laptop or notebook computers are now commonplace on expeditions. They are now reasonably reliable and robust and, compared with much scientific
equipment, they are not expensive. Their power
requirements are not great. If generators are being
taken there is no problem; otherwise their batteries
can be recharged from solar panels if necessary.
Therefore there need be no hesitation in including
computers in expedition equipment. Like all battery
operated apparatus they work better at comfortable
temperatures but are no more fussy than EGG
machines, for instance. Computers have many applications, from writing reports to online control of
other equipment. They are good for storing data, on
or off line with backup on discs. If more than one
computer is to be taken, as is likely, it is worth ensuring that the same programs are installed on all of them
so that one can act as a backup for any other machine.

32.9
OTHER AREAS OF SCIENTIFIC
STUDY
The areas of research mentioned are the classical ones
for altitude research. As more workers from different
fields have become interested in the effects of altitude
hypoxia on other systems of the body, more techniques have been used in the mountains.
Psychomotor testing equipment has changed from
clipboard, stopwatch and pencil to computers. Visual
field testing, audiometry and measurement of balance or sway have been made using computer based
systems. Overnight cough frequency has been monitored with voice activated battery tape recorders and
cough threshold measured with nebulized citric acid
solutions. Even near-infrared spectroscopy has been
used to measure brain oxygenation at altitude in the
field (Morgan et al. 1999). All these applications of
modern electronics, and others, show how the possibilities for research at altitude have expanded. The
future of the subject is only limited by the imagination of researchers and should be bright indeed.

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Index

NOTE: this index covers pages 1-364 (pages 1-21 cover the historical background). American English spelling is used, eg 'edema'. Page
numbers in italics refer to figures or tables.
abortion 204
abscesses 327
acapnia 158
accidents at altitude 318-19
acclimatization 44-6, 284-5
adaptation 46
and adrenergic response 186
age, gender and experience 49
and alveolar gases 57-8
ascent rate 48
deterioration 37, 44, 46, 282
experience as factor 49, 57
and hematology 97
and hypoxic ventilatory response (HVR) 53-5
inadequate 78
and individual variability 49
longer term (highlanders/lowlanders) 64
oxygen transport system 46-8
physiological response to hypoxia 44-5
practical considerations and advice 48-9
pre- and carry-over acclimatization 49
respiratory 58, 62
tissue 120
to heat 290
women 330
ACE see angiotensin converting enzyme
acetazolamide 113, 156, 159, 190
and acute mountain sickness 227-8, 229
and HACE 249
acetylcholine 53, 193
acetylene rebreathing method 82, 84
acid-base balance of blood 108, 109, 116-18, 149-50
in COPD 352
physiology at extreme altitude 149-50
see also hemoglobin, hemoglobin-oxygen affinity
acidosis 52, 63, 166
Acosta, Joseph de 3-5, 4, 23, 143
acrocyanosis 320
ACTH see hormone, adrenocorticotropic
acute mountain sickness (AMS) 7, 45, 48, 50, 55-6, 101, 215-16
and acapnia 158
acetazolamide 166, 227-8, 229
and anorexia 169, 226
anorexia and leptin 226
aspirin and dexamethasone 228, 229
and atrial natriuretic peptide (ANP) 184
cerebral blood flow 194, 220, 224
in children 332, 333-4
coca 229
consistency in response to altitude 218

definitions and nomenclature 216-17

derangement of clotting mechanism 225
dexamethasone and aspirin 228, 229
diffusing capacity for carbon monoxide 75
etiology 218-21
exercise 220-2
at low altitude 221
and fitness 218
fluid balance 221
fluid intake 227
gender, age and body build 219
ginko biloba 229
and RAPE 2 37, 241
high carbohydrate diet 176
and hormones 178
hypoxic pulmonary artery pressor response 219-20
and hypoxic ventilatory response (HVR) 55-6, 219
incidence of benign AMS 217-18
individual susceptibility 218
intracranial pressure 224-5
leptin and anorexia 226
mechanisms 221-6
microvascular permeability 225-6
nifedipine 228-9
nonsteroidal anti-inflammatory agents 229
oxygen saturation 220
oxygen treatment 229
oxygen-enriched sleep 167
paracetamol 229
prophylaxis 226-9
rate of ascent 226-7
rest 229
roleofP G 0 2 224
signs and symptoms 217,230, 231
smoking and diet 219
sodium and water balance 222-4
spironolactone 228
sumatriptan 229
telescope sites 340
theophylline 229
treatment 229-31
and weight loss 171
see also high altitude pulmonary edema
adaptation 44, 46, 98
ADH see hormone, antidiuretic
adrenal glands 185
adrenarche 206
adrenosympathetic system 185-6, 288-9
Afghanistan 33
Africa, mountains of East and South 34

418 Index
age factor
in acclimatization 49
in acute mountain sickness 219, 334
and body temperature 276
in chronic mountain sickness 253-8
elderly people 287, 296, 301, 329, 334-5
in high altitude population 203
and HVR 53
see also children; infants; women
air
as insulation 41
movement and thermal balance 274
pressure 23
see also barometric pressure
thinness 23, 31
see also atmosphere; humidity; oxygen, enrichment of room air
air pump 23-4
airway
expiratory positive pressure 239
obstruction 92
rewarming for hypothermia 302, 319
Alaculuf Indians 285
albedo 31,275
albinism and sunburn 292
Albutt, T. C. 9
alcohol 210, 283,297
aldolaseA102
aldosterone 99, 101, 180-3, 222-3
alimentary system 288, 353
alkalosis
respiratory 60, 63, 65, 73, 74
and acapnia 158
and extreme hyperventilation 107, 142
metabolic compensation for 108, 113-14, 116, 118
renal compensation for 190
uncompensated 136
almitrine 166
aloe vera cream 315
Alpine Club 8-10
Alps, European 9-10, 33, 34, 38
altimeter calibration 25, 26
altitude
and athletes 345-9
and barometric pressure see barometric pressure and
altitude
consistency in response to 218
definition and relevant areas 33-4
effect on plasma volume 101-2
and endothelin 188
and erythropoiesis 102-3
and frostbite 313
and hemoglobin concentration 103-6
medical conditions at 322-3
see also individual conditions
physiology of extreme 145-52
platelets and clotting at 106
and red cell mass 103
and serum EPO concentration 102-3
white blood cells and 106
alveolar epithelial cell 68
alveolar gases
and acclimatization 57-8
effect of altitude 58, 147-8
and research 358, 361
alveolar partial pressure of carbon dioxide 24, 37, 51, 147-9
alveoli 66, 70, 92
ambient to inspired partial pressure of oxygen 47

American Medical Research Expedition to Everest (1981) 28,29,

31,56
and abnormal rhythm 88
CNS function 197, 198
diffusion limitation of oxygen 77
electrocardiographic changes and pulmonary hypertension 95
energy intake and weight loss 170
maximal oxygen uptake measurements 132,139, 140
and oxygen affinity of hemoglobin 108-9, 113,114
periodic breathing 162, 165
respiratory alkalosis 74
ventilation 133
amino acids 111, 127,193
amnesia 235, 297
see also memory impairment
amputation for frostbite 315
AMREE see American Medical Research Expedition to Everest
(1981)
AMS see acute mountain sickness (AMS)
anaerobic performance and exercise 141
Andes (South America) 4-5, 28, 33, 34, 35
chronic mountain sickness 255
clothing 41
hemoglobin concentration 104
high pulmonary diffusing capacities (natives) 75
houses and shelter 41
HVR and altitude residents 55
population 42
rainfall 36
serum immunoreactive EPO concentration 103
see also individual places eg. Cerro de Pasco; Lima (Peru)
anemia 98, 104, 195,325,355
see also sickle cell disease
anesthesia at altitude 260, 268-70
avoidance of hypoxia 268
and HVR 53
hypoxic ventilatory drive 269
postanesthetic period 270
practical considerations 26970
vaporizers 269
Ang Rita, Sherpa 28, 30
angina 89, 210, 287,296
angiogenesis 102
angioplasty 323
angiotensin 92, 99, 101, 180-3
angiotensin converting enzyme (ACE) 180
Anglo-American Expedition to Cerro de Pasco (1921-2) 108
see also Cerro de Pasco
animals
husbandry 38, 43
and intracellular enzymes activity 127
and myoglobin concentration 127
and oxygen affinity of hemoglobin 74, 11011
and pulmonary hypertension 89
pulmonary pressor response 209
see also birds; individual animals eg. llama; vicuna
anorexia 168,169, 171, 217, 226
anoxia, focal 122
ANP see atrial natriuretic peptide
Antarctica 34, 38
antibiotics 238, 292, 315
anticoagulants 265, 315, 326
aortic body 51, 52
aphasia 260, 264-5
apneaSS, 156, 158, 159, 163
appendicitis, recurrent 327
appetite loss 46, 168, 176-7, 248

Index 419
Arctic Circle and temperature 37-8
Argentina 35
arginine vasopressin, urinary 180
Arrhenius's law (heat production) 272
arrhythmia, sinus 81, 163
arterial leakage in HAPE 244
arterial oxygen saturation 51, 165, 209
arterial to mixed venous partial pressure of oxygen 48
arteriosclerosis of aorta 210
artery, pulmonary see pulmonary artery
ascent rate 48, 196, 217-18, 237
see also descent rate
Asia, central 5-8
asphyxia 319
aspirin and dexamethasone in AMS 228
asthma
at altitude 325
and cold stress 288, 320
ataxia 230, 248
atherosclerosis 210
athletes
and altitude training 346, 349
critical partial pressure of oxygen for hematological adaptation
348
detraining and hypoxia 347-8
and HVR 53
immune response 348
'living high, training low' 348
measuring effects of training 348
mountaineers as 346
polycythemia and increased hematocrit 347
Atlas mountains (North Africa) 33
atmosphere 22-3, 25
model 29-30
standard 25-6, 146
see also barometric pressure and altitude
atrial natriuretic peptide (ANP) 99, 183-4, 223, 287
atrial pressure 87, 99
atrial septal defect 325, 354
atrial/ventricular contractions, premature 81,88
atrium, right 99
Aucanquilcha mine, Chile 29,132, 177, 196, 337
Australian aboriginal bushmen 285
autonomic nervous system 86
avalanches 319
AVP see arginine vasopressin; plasma arginine vasopressin
babies see birth defects; children; fetus; infants
bacteria and solar radiation 211
ballisto-cardiography 82
balloonists 10, 45, 192
balloons
intracolonic/intragastric 302-3
radiosonde see radiosonde balloons
Baltistan 34
Barcroft, Joseph 67, 74, 76, 131
and cardiac output 82
on oxygen dissociation curve 108, 11 1-12
on quality of sleep 157, 158
Barcroft Laboratory, California 29
and oxygen enrichment of room air and CNS 200-1
barometers 23, 29
barometric pressure and altitude 23-4,28,29, 146-7
factors other than 30-2
history 23-4
inspired partial pressure of oxygen 30
for locations of importance 28-9

logarithmic relationship for determining 24

model atmosphere equation 29-30
physical principles 24-5
physiology 30, 146-7
relationship between 22-3
relationship of standard atmosphere 26
and vaporizers in anesthesia 269
variation of pressure
with latitude 26-8, 29, 142
seasonal 27-8, 146
barotrauma 23
behavior and mood changes 192
Ben Nevis (Scotland) 37
benzodiazepine 166
benzolamide 228
Bernese Oberland (Switzerland) 38
Bert, Paul 8, 22, 23, 24, 45, 82
barometric pressure 146
on increase in red blood cells 97
on oxygen and carbon dioxide dissociation curves 107, 355
tissue changes 120
beta-adrenergic adaptation 150
beta-adrenergic receptors and hypoxia 86
beta-blockers 86, 181
Bhutan 41
bicarbonate concentration 50, 59-63, 141
active transport of 61
mechanisms for reduction 60-2
passive transport of 62
reduction at altitude 60, 116
bicarbonate ion excretion 118
bigeminy, atrial 88
birds 111, 124
birth defects 210
bivouacs and tents 319
bleeding from mouth/eyes/nostrils 82
blindness 41,261
blistering of skin 292, 308-9, 314
blockers, metabolic 52
blood
acid-base status 108,109, 116-18, 149-50
alkalinity 108, 109, 112
alterations of acid-base status 107, 108
bleeding from mouth/eyes/nostrils 82
brain blood flow 56, 105
effect of acute hypoxia 63
cerebral blood flow
in AMS 194, 220, 224, 228
and COLD 353
and hypoxia 193-5, 224
changes at Everest summit 153-5
clotting/coagulation 225, 245, 261-3
derangement of mechanism 225, 291
coughing up blood 263, 264
hemodilution 105-6
increased viscosity 103, 105, 195
intravascular changes in extreme cold 287
lactate levels 131-2, 149-50, 358-9
physiological changes and acclimatization 107
platelets and clotting 106, 261-2
pulmonary capillary 65, 135
red blood cells 68, 97
cell mass (RCM) 45, 103, 226-7
filterability of 105
increase in 97-8
see also 2,3-diphosphoglycerate; lactic acid
reinfusion and performance at altitude 106

420 Index
blood cent.
systemic blood pressure 89
white blood cells 106
see also hemoglobin; hemoglobin concentration; plasma
volume; polycythemia
blood disorders at altitude 325-6
blood gases
and acid-base balance 352
and chronic mountain sickness 254
in HAPE 236
see also blood gas; blood-gas barrier
blood glucose control at altitude 187-8
blood loss and hypoxia 989
blood pressure and extreme cold 89, 287
blood sampling and storage in field studies 363-4
blood vessels in frostbite 310-13
blood-brain barrier 61
blood gas
dissociation curve 73, 107
values in high altitude natives 117
blood-gas barrier 65, 68, 70-1, 121
diffusing capacity of 135
and vascular remodeling 94
Blue Beryl (Tibetan medical text) 3
blunting of HVR see hypoxic ventilatory response, blunting
BMR see metabolism, basal metabolic rate
body composition and weight loss 172-4
fat absorption and hypoxia 174
malabsorption at altitude 174
protein absorption and hypoxia 174
Bohr, Christian 66-7, 70, 77
Bohr effect 108, 109, 110, 111, 113
oxygen dissociation curve 108
Bolivia 80, 89, 97, 104,132, 186
bone marrow disorders 98
bones and joints in frostbite 312
see also orthopedic conditions at altitude
bowels see alimentary system; gastrointestinal disorders
Boyle, Robert 23-4
Boyle's law 24
bradykinin 178, 189
brain
acid-base balance 62-3
blood flow 56
damage to nerve cells 122
extracellular fluid (ECF) 50, 55, 59
histological changes in hypoxia 193
intracellular pH 63
intracranial pressure and AMS 224-5
local brain ECF 62-3
mechanisms of action of hypoxia 192-5
oxygenation at high altitude 195
and sleep 160
tumour 261
see also central nervous system; mental performance
brain death and hypothermia 298
breathing
Cheyne-Stokes 157
in COLD 351-2
periodic 57, 88, 157-8, 159, 160-7, 216
characteristics 160-2
effects of drugs 166-7
gas exchange 165-6
mechanism 164-5
reaction theory of breathing 109
sensing systems for chemical control 51
see also sleep; ventilation

breathlessness 45
see also hypoxia
brisket disease (edema in cattle) 82, 209
British Mount Everest Medical Expedition (BMEME 1994) 267-8
British Winter Everest Expedition (1992) 170
bronchioles, terminal 66
bronchitis, chronic 166, 211-12, 325
bronchoconstriction 288
bronchopleural fistula 263
bronchospasm through exercise 288
BTPS (body temperature, ambient pressure, saturated with water
vapor) 131, 133
bupivacaine, epidural 314
business at altitude see commerce at altitude
Cairngorms (Scotland) 37
calcium 52
calcium channel blockers and HAPE 238, 244
calcium homeostasis 193
calories 170
camels 38
cancer
of heel after frostbite 316
of skin 292-3
of thyroid 208
Capanna Regina Margherita (Italy) 29, 67, 108, 109, 113
adrenosympathetic system 185-6
breathing measurements 157-8
capillaries
density 123-5, 137,172
muscle capillary tortuosity 122-4
oxygen diffusion to mitochondria 137
pulmonary 68, 68, 70
rate of oxygen uptake 70-2
stress failure 242-4
in pulmonary circulation 94
systemic 48
capillarization, increased 120
capillary endothelial cells 68
capillary wall remodeling 94
carbohydrates 175, 219, 331
carbon dioxide 52
and control of breathing during sleep 163
diffusion through tissues 121
dissociation curve 107
dynamic response 63-4
and lung diffusion 65
partial pressure see partial pressure of carbon dioxide
response line 50
ventilatory response and acclimatization 58, 62
see also partial pressure of carbon dioxide
carbon monoxide 65, 66-7
diffusing capacity 69, 75, 150-1
reaction with hemoglobin 75
carbonic acid in blood 108
carcinoma see cancer
cardiac arrest owing to cold 298, 300
cardiac catheterization 236-7, 362
cardiac conditions
with altitude risks 324-5
low output 3545
cardiac infarction at altitude 323
cardiac massage 300
cardiac output 48, 81, 83, 150
acetylene rebreathing method 82, 84
at extreme altitude 150
and autonomic nervous system 86

Index 421
cardiac index against oxygen uptake 84
and optimum hemoglobin concentration 105
and oxygen consumption 84, 85
and stroke volume 87, 297
and work rate 82, 87,130
cardiac tamponade 183
cardiology and clinical lessons from high altitude 356
cardiomyopathy 354
cardiovascular system
adaptations at high altitude 208
diseases 210-11
disorders at altitude 323-5
reaction to extreme cold 286-8
responses to exercise 136
right ventricular hypertrophy 208
carotid body 44, 51, 52-3
anatomy and physiology of 52-3
and chemodectoma 208
denervation of 53, 57, 62
and erythropoiesis 99
and reabsorption of sodium 102
catecholamines 92, 178, 185-6, 245, 296, 331
Central Asia 5-8
central nervous system 45, 53, 57, 59, 122
function at high altitudes 196-7
function at moderate altitudes 195-6
mechanisms of action of hypoxia 192-5
oxygen enrichment and neuropsychological function 200-1
psychomotor performance 196-7
residual impairment following return from high altitude
198-200,799
summary and history 191-2
see also brain; chemoreceptors; mental performance
Central and South America 3-5
cerebral edema see high altitude cerebral edema (HACE)
cerebrospinal fluid (CSF) 50, 59-60
bicarbonate concentration 60, 61-2
lack of stability of CSF pH 63
cerebrovascular accidents at altitude 261
Cerro de Pasco (Peru) 29, 67, 74, 75, 82, 84, 89
enzymatic activity of muscle 127
mining community 337
mitochondrial density 126
myoglobin concentration 126-7
oxygen affinity of hemoglobin 108, 111, 113
peripheral tissue changes 121
plasma volume 102
pulmonary arterial pressure 93
Certec bag 240
Charles' law (of gases) 25
chemodectoma and carotid body 208
chemoreceptors
central medullary 59
hypoxia stimulating ventilation 109
peripheral 44, 45, 51, 52-3, 60, 63-4, 166
HVR and acclimatization 53-4
and hypoxic drive 135
and sleep 160
see also aortic body; carotid body
chemotransduction 52
chest development 76, 206
chilblains 320
children
at altitude 329, 331-4
cyanotic heart disease 354
diagnosis of AMS 231
frostbite in feet 316

growth through childhood 205-6

high altitude natives 76
patent ductus arteriosus 210, 354
see also infants
Chile 29, 35, 82, 104, 108, 337-8, 340-1
Chimborazo, Mount (Andes) 82, 143
Chinese Expedition to Everest (1975) 95
Chinese Headache Mountain story 3
chloroform 269
chloroquine 292
cholecystokinin (CCK) 168, 226
chronic bronchitis see bronchitis, chronic
chronic mountain sickness (CMS) 43, 104, 105, 184, 253-8
age factor 257-8
clinical aspects 254-6
consensus group on CMS 256
epidemiology 255-6
and gender 257
hemodynamics and pathology 254
history 253-4
hypoxic ventilatory response 257
investigations 254
and lung disease 256-7
lung disease and polycythemia 256
mechanisms 256-8
and 'Monge's disease' 256
with normal lungs 257
polycythemia of altitude 256
prevention 254
and sleep 257
symptoms and signs 254
terminology 256
treatment 255
chronic obstructive airway disease 213
chronic obstructive lung disease (COLD) 325, 351-3
alimentary system 353
blood gases and acid-base balance 352
cerebral blood flow (CBF) 353
circulation 352-3
fluid balance and peripheral edema 35
hematological changes 352
mental effects 353
and proteinuria 190
symptoms 351-2
chronology of principal events 2
circadian rhythm and body temperature 276
citrate synthase 129
citric acid 127, 267
climate 34-5, 36, 37, 295
climbers and hypoxic ventilatory response (HVR) 57
CLO see thermal balance and regulation, insulation
clothing 38, 41-2, 275, 279-81, 284
for children 333
and frostbite 317, 318
protective glasses/goggles 292
clubbing of fingers 253
CMS see chronic mountain sickness
CNS see central nervous system
coagulation of blood see blood, clotting/coagulation
coarctation of aorta 324
coca in acute mountain sickness 229
cognitive-perceptual-motor battery test, repeatable 198
COLD see chronic obstructive lung disease
cold
adaptation at high altitude 209
allergy 320
and children 333

422 Index
cold cont.
conditions associated with cold stress 320-1
and fatigue 289
human response to 43, 283
regular exposure to 283
tolerance 285
women and 331
see also hypothermia; thermal balance and regulation; thermal
extremes, reaction to cold
cold injury 12, 31,294-5
cold water immersion 296, 317
fibrosis following 316
nonfreezing 294, 317-18
avalanches, crevasses and bivouacs 318-19
pathophysiology, prevention and treatment 318
phlebitis and arteritis 286
and respiratory tract 288
collagen 94
Collahuasi mine, Chile 29
colloid, retention of 211
Colombia 185, 189
Colorado see Pikes Peak expedition (1911)
commerce at altitude 336-7
common carotid artery 52
computers in field studies 364
concentration in extreme cold 289
conduction in thermal exchange 275
congenital heart disease 210
conjunctiva 254, 291-2, 312
consciousness loss see hypoxia
containers see storage of samples in field studies
contraceptives, oral 331
contractility, myocardial see myocardial contractility
convection in thermal exchange 273, 274
cor pulmonale 212
cornea 41, 261, 266-7, 291, 312
coronary artery disease 323
coronary by-pass surgery and altitude 323
coronary circulation 88-9
corticosteroids 178, 184-5, 239, 303
cortisol, endogenous 183
cortisone 185
cosmic radiation 32
cough 253, 259, 263, 264, 267-8
cretinism 213
crevasses 319
Crohn's disease 326
Crooked Creek, California 29
crops and population 39
CSF see cerebrospinal fluid
cyanate and oxygen dissociation curve 114
cyanosis 99, 234, 253, 254
cyanotic heart disease 190, 354
cystic fibrosis 325
cytochrome oxidase 129
cytochromes 52, 122
cytokines and AMS 226
cytoplasm 121-2,128
D-xylose absorption 174
Dalton's law (of gases) 25
Darjeeling (Himalayas) 36, 37
deafness 213
death, deceptive appearance of 294, 298, 300
Death Valley, California 111
decompression 23, 51, 58, 146, 358-9
defibrillation see ventricular fibrillation

dehydration 31, 99, 101, 107, 282

chronic 118
in frostbite 314
and hypothermia 297
and myoglobin concentration 127
risk factor for thrombosis 263
density of air see air, thinness
dental conditions 214, 327
desaturation during sleep 165
descent rate 238, 249, 254
see also ascent rate
deterioration, altitude 37, 44, 46, 282
deuterium 170
dexamethasone 185, 228, 229, 239, 240, 248, 249
diabetes mellitus 326
Diamox (acetazolamide) 227
diaphragm 23, 121, 126
diarrhea 326
diathermy for rewarming 303
diazepam 166
diet 168, 170, 175-7
and acute mountain sickness 219
in high altitude population 40, 211, 214
diffusion see pulmonary diffusion
diffusion in peripheral tissues 121-9
principles 121-2
tissue partial pressures 122-3
digit vigilance task test 198
digoxin 239
dilatation of heart 82
dilatation and rupture of superficial blood vessels 23
dimethylchlortetracycline 292
2, 3-diphosphoglycerate 107, 108, 109-10, 111, 113, 154
diplopia 248
diseases at high altitude 209-14
see also individual diseases
dislocation and frostbite 314
disorientation 294
distension of intestinal gas 23
diuresis 101, 102, 287
diuretics 238, 249, 292
dizziness 230
dopamine 53, 190, 301
doping (blood reinfusion) 106
Doppler ultrasound and cerebral blood flow 194
doxapram 270
drugs
and acute mountain sickness 227-31
effect on cerebral blood flow 195
effect on sleep at high altitude 166-7
for frostbite 315
for high altitude cerebral edema 249
for high altitude pulmonary edema 238-9
for hypothermia 303
nonsteroidal anti-inflammatory 327
see also individual drugs
dwellings 38, 41
see also shelter; tents and bivouacs
dynamic carbon dioxide ventilatory response 64
dysphasia 259, 260
dyspnea 253, 351
dysrhythmia 88
dzo 209
ECF see extracellular fluid
EGG see electrocardiography
echocardiography 88, 362

Index 423
economics 38-9
edema 82, 312
cellular 250-1
cytogenic 250
of face 253, 288
in frostbite 312
peripheral 217,230
subclinical 221,234
vasogenic 250
see also high altitude cerebral edema (HACE); high altitude
pulmonary edema (RAPE); pulmonary edema
EEC see electroencephalogram
eicosanoids 225-6
elastin 94
elderly people see age factor, elderly people
electrocardiography 81, 88
changes and pulmonary hypertension 94, 95-6
in field studies 362
in high altitude pulmonary edema 235
in hypothermia 298
electroencephalogram abnormalities 198
electrolyte abnormalities in hypothermia 303
electrolyte balance 221
electron transport chain 52, 128-9
emphysema 166, 212, 239
empyema 263
endocrine system 178-9
adrenergic response and acclimatization 186
adrenosympathetic system 185-6
altitude and atrial natriuretic peptide (ANP) 183
antidiuretic hormone (ADH) 179-80
control of blood glucose 187-8
corticosteroids (and case study) 184-5
endothelin 188-9
renin-angiotensin-aldosterone system 180-3
thyroid function and altitude environment 186-7
see also renal system
endothelin 178, 188-9
energy balance at altitude 169-70, 273-4, 275
expenditure due to exercise 169-70
measurement technique 170
intake and caloric balance 170
output 169
enflurane 268
enolase-1 102
ENT conditions at altitude 327
environment and frostbite 312
enzymes 121, 180
at extreme altitude 129
intracellular 127-9
thrombolytic 315
epilepsy at altitude 328
epinenephrine 86, 186, 289
epithelial cells 66
EPO see erythropoietin
equipment in field studies 360-4
ERPF see renal system, effective renal plasma flow
erythropoiesis 98, 102, 102-3, 106
erythropoietin (EPO) 98, 258
'Eskimo lung' 287
Ethiopia 33, 34, 35-6, 42, 204, 212
euglobulin lysis time 225
Evans' blue method (plasma volume) 101
evaporation 38, 275
Everest, Mount
accounts of exercise at very high altitudes 131
barometric pressure and altitude 22, 24, 26, 27, 28

cardiac output at Base Camp 84

Chinese Expedition (1975) 95
history of attempts 13-15
HVR and height reached 56
limitations to oxygen uptake on summit 153-5
measurement of barometric pressure 28-9, 74
Operation Everest I 49, 76, 144
Operation Everest II 49, 78, 79, 84, 85-6, 87, 90
CNS impairment 200
exercise and other measurements 133
intracellular enzymes 129
maximal oxygen uptake 140
mitochondrial density 126
oxygen affinity of hemoglobin 114
physiology at extreme altitude 146
weight loss 172
ventilation levels 31
water vapor pressure 30
weight loss in Western Cwm 171
winter temperature at summit 38
see also individually named expeditions
evoked potentials 193
exercise 130-3
and acclimatization 48, 49
and acute mountain sickness 220-2
anaerobic performance 141
and antidiuretic hormone 179
arterial blood gases 136-7
and atrial natriuretic peptide 183-4
and barometric pressure 146
cardiovascular responses 136
causing changes in oxidative enzyme systems 127-8, 129
energy expenditure 169-70
and fall in oxygen saturation 56
and high altitude pulmonary edema 238
and hypothermia 297
limitation of performance at extreme altitude 152-5
and lung diffusion 65, 73,135
maximal oxygen uptake at high altitude 139-41
and myoglobin concentration 127
oxygen diffusion as factor limiting exercise 137
peripheral tissues 137-9
and plasma volume 100-1
reninangiotensin-aldosterone system 178, 1812
and thermogenesis 277
and ventilation 133-5, 207, 359
ventilation/perfusion relationships 135-6
exhaustion and hypothermia 297-8
expeditions, medical and physiological 15-19
experience as factor in acclimatization 49, 57
expiratory positive airways pressure 239-40
explorers
early 2, 3-12
medical and physiological expeditions 2, 15-19
extracellular fluid (ECF) 50, 55, 59, 101
acid-base status of 109
increase in 181
eye conditions 259, 261, 2657
blurring of vision 248
chronic eye infections 212
congestion of conjunctivae 254
corneal surgery and altitude 266-7
'cottonwool' spots 265
diplopia 248
in frostbite 312
myopia 266-7
papilledema 248, 265

424 Index
eye conditions cont.
retinal hemorrhage 248, 265-6
snow blindness (photophthalmia) 41, 261, 291-2
visual perception impairment 196
face creams, protective 315
Falklands War 295
Pallet's tetralogy 324, 354
fasciotomy 314
fat
hypoxia and fat absorption 174
and thermogenesis 276, 277, 296
fatigue 46, 129, 131,230,289
fats 176
feet see frostbite
fertility 203-4
fetus
growth of 204-5
hemoglobin in 73, 110, 111
oxygen in 80
pulmonary hypertension in 95
pulmonary vasoconstriction 90
fibrinogen 262
fibrin(ogen) fragment E 225
fibrinopeptide A 225
fibroblast growth factor, basic 94
nbronectin 94
Pick principle 66, 82, 138
Pick's law of diffusion 68-9, 70, 121
field studies 357-8
blood sampling and storage 363-4
cardiological measurements 362
computers 364
cost 359
electricity supply 360-1
hematology 364
laboratory accommodation 360
personnel management 359
planning, testing and practice 357-8
respiratory measurements 361-2
sleep studies 362
versus chamber studies 358-9
water and reagents etc. 361
fingers, tingling 45
First International High Altitude Expedition (1910) 158
fissure-in-ano 327
fluid balance
in AMS 221-4, 227
in extreme cold 287-8
and peripheral edema 352
fluid loss from lungs 31
fluid volume in hypothermia, intravascular 304-5
follicle stimulating hormone (FSH) 189
food see crops and population; diet; nutrition and intestinal
function
Fournier's law of heat transfer 271-2
fractures and frostbite 314
frostbite 263-4, 306-17
after effects 316-17
and altitude 313
amputation 315
bones and joints 312
classification 307
clinical features 307-10
deep 309-10
dehydration 314
distribution 307

environmental factors 312

epidemiology 307
eye disorders 312
factors concerned with 307, 312-13
feet 316-17, 318
frostnip 313
gangrene 310, 315, 317, 318
investigations 314
pain relief 314-15
pathophysiology 310-12
polar hands 316-17
prevention 313, 318
superficial 308-9
surgery 314, 315
thawing procedure 314
trauma 315-16
treatment 313-16, 318
see also cold injury, nonfreezing; thermal extremes, reaction to
cold
frusemide 248
FSH see follicle stimulating hormone
furosemide 227
G-suits 99
Galileo Galilei 23
gallstones 210
Gamow bag 240
gangrene see frostbite
garlic, eaten for high pulse rate 82
gas changes at Everest summit 153-5
gas exchange during periodic breathing 165
gases 24-5
see also blood gases and individual gases eg. helium; nitric oxide
gastrointestinal disorders 230, 288, 326-7
gender
and body temperature 276-7
and chronic mountain sickness 257
distribution in high altitude population 203
factor in acclimatization 49
see also women
genetic adaptation of animals 111
genetic factors and hemoglobin concentration 104
geography and human response to altitude 33-43
Andes of South America 35
Ethiopian highlands 35-6
European Alps 9, 34
Himalayas and Tibetan plateau 34
see also climate; clothing; cold; dwellings; economics; load
carrying; population; rainfall; temperature; terrain
ginko biloba in acute mountain sickness 229
glasses, protective 292
glomus cells (type I) 52
glossopharyngeal nerve 53
glucagon 178, 189
glucose
cerebral metabolism of 61
and diabetes mellitus 326
and hypothermia 303
glucose transporter-1 102
glycerol trinitrate 92
glycogen synthesis 46
glycolysis 102, 129,128, 150
anaerobic 122, 131, 136
gods, mountain 34, 35
goggles, protective 41, 42, 292
goiter 34, 187,212-14
Graham's law (of gases) 25

Index 425
granulocyte count 106
grass 38
gravity, zero 99
guanylate cyclase 92
gulf stream 37
HACE see high altitude cerebral edema
HAGA see high altitude global amnesia
Haldane, J. S. 25-6, 51, 66-7, 82, 109, 131
hallucinations 248, 289-90
halothane 269
Halstead-Reitan battery test 198
Halstead-Wepman aphasia screening test 198
hands 286,315, 316-17
HAPE see high altitude pulmonary edema
Hawaii 34
HCVR see hypercapnic ventilatory responses (HCVR)
headache 217,230, 231, 248, 264, 328
with transient aphasia 260
see also migraine with ophthalmoplegia
heart
dilatation of 82
see also cardiac...; cardiovascular...
heart disease
congenital 210
cyanotic 354
heart rate 45, 85-7
and hemoglobin concentration 87
maximal 85-6
and oxygen breathing 87,134
in periodic breathing 161, 163
of porters 40
response to hypoxia 45, 85,208
and stroke volume 87
see also cardiac output
heart rhythms, abnormal 81
heat exchanger for rewarming 302
heat exhaustion/stroke 291
heat regulation of body 38, 277-82
clothing 279-81
countercurrent heat exchange 278
heat conservation 278-82
heat injury 290-1
heat production and loss 277-8
insulation 278-9
and oxygen consumption 281
shelter 282
snow blindness (photophthalmia) 291-2
solar radiation 291-2
see also thermal balance and regulation; thermal extremes,
reaction to heat
height and growth 205-6
height limit of climb without supplementary oxygen 155
helium 25, 69
hematocrit 254-5, 263, 265, 311, 347, 348
hematology 97-8, 236, 352, 355-6, 364
hematoma, perianal 327
heme group 53
heme oxygenase 102
hemiplegia 260
hemodilution 105-6, 265
hemodynamics of chronic mountain sickness 254
hemoglobin
and carbon monoxide 65
fetal 73
hemoglobin-oxygen affinity (P50) 74,107, 108, 109-16, 139
increase in flow 81

mutant hemoglobin (Andrew-Minneapolis) 73-4, 111, 114

oxygen affinity and diffusion limitation 73-4
reaction rates with oxygen 69-70
regulation of concentration 98
see also blood
hemoglobin concentration 24
and altitude 103-6, 207-8
and cardiac output 85, 85
and climbing performance 106
on descent from altitude 106
in HAPE 236
and heart rate 87
increased 39, 44, 45, 48, 75, 97-8
lowlanders going from sea level to altitude 1034
optimum 105-6
phenotypic variance 104
and plasma volume 100,102
polycythemia of high altitude 105
residents at altitude 104-5
in sickle cell disease 214
see also blood
hemoglobinopathies with altered oxygen affinity 355
hemorrhage
alveolar 244
gastric 326
retinal 265-6
splinter 263
and temperature regulation 282
hemorrhagic disorders 211
hemorrhagic hypovolemia 315
hemorrhoids 327
Henderson-Hasselbach equation 59, 60,116
herbal medicine for AMS 229
hernias 327
hexokinase 129
HIF-1, hypoxia and erythropoiesis 102
high altitude cerebral edema (HACE) 217, 223, 247-8
cellular edema 250-1
clinical presentation and 4 case histories 248-9
cytogenic or vasogenic cerebral edema 250
incidence and etiology 250
investigations 249
mechanisms 250-1
nitric oxide and cerebral edema 251
postmortem appearance 250
symptoms and signs 248
treatment 249
vascular endothelial growth factor 251
venous thombosis 250
high altitude global amnesia 261
high altitude populations see population at high altitude
high altitude pulmonary edema (HAPE) 56, 92, 136, 217, 232-5,
325
2 case histories 234
antibiotics 238
and antidiuretic hormone 179
arterial leakage 244-5
and atrial natriuretic peptide 184
blood gases 236
blood pressure 235
calcium channel blockers 238
cardiac catheter studies 236-7
clinical presentation 233-7
defective transepithelial ion transport 246
descent as treatment 238
diuretics 238
drugs 238-9

426 Index

high altitude pulmonary edema (HAPE) cont.

edema fluid 241
electrocardiography 235
etiology and susceptibility 237
exercise 238
expiratory positive airways pressure 23940
hematology 236
hypoventilation 245-6
hypoxia 245
incidence 234
infection 246
inflammation as factor 245
introductory history 232-3
left ventricular failure 242
mechanisms 241-6
multiple pulmonary emboli 245
neurogenic pulmonary edema 246
nitric oxide 239
outcome 240
oxygen as treatment 238
pathology 241
and periodic breathing 165
portable hyperbaric chamber 240
postmortem examination 241
prevention 237-40
pulmonary hypertension 242
radiology 235
release of mediators of inflammation 225
and retinopathy 266
signs 235
slow ascent as prevention 237
stress failure of pulmonary capillaries 242-4
symptoms 234-5
treatment 238-40
uneven pulmonary vasoconstriction and perfusion 242
urine 236
vascular permeability 245
vasodilators 239
venular constriction 244
highlanders and acclimatization 20-1, 64
Hillary, Edmund 38,144
Himalayan mountains 7, 28, 33, 34-5, 95
chronic mountain sickness 255
see also Everest, Mount
Himalayan Scientific and Mountaineering Expedition (1960-1)
(Silver Hut) 76-7, 83, 84, 85, 88, 96, 102
diffusing capacity of blood-gas barrier 135
EEC measurements 198
exercise 132
mental performance at very high altitude 197
muscle atrophy 125
oxygen affinity of hemoglobin 108
physiology of extreme altitude 145-6
vaporizers in anesthesia 269
weightless 171
hippocampus 193
histamine 92, 93
history of high altitude medicine 1-21
acute mountain sickness 215-16
Alpine Club 8-10
balloonists 10
blood gas transport and acid-base balance 107-9
cardiovascular system 81-2
Central Asia 5-8
central nervous system 192
Central and South America 3-5
Chinese Headache Mountain 3

chronology 2
cold injury 12
Everest 13-15
exercise 131-3
explorers and physiologists 10-12
high altitude pulmonary edema 232-3
indigenous high altitude dwellers 20-1
laboratories 19-20
limiting factors at extreme altitudes 143-5
lung diffusion 66-7
medical and physiological expeditions 15-19
neurovascular disorders 260-1
oxygen secretion 12-13
peripheral tissues 120-1
sleep 157-8
homeostasis, calcium and ion 193
homes see dwellings
hormone
and acute mountain sickness 178
adrenocorticotropic (ACTH) 178, 183, 185
antidiuretic (ADH) 99, 179-80
inappropriate secretion at altitude 180
follicle stimulating 189-90
growth 178, 189,289
luteinizing 189-90
prolactin 189
responses to extreme cold 288-9
testosterone 189-90
hospital treatment of hypothermia 300-3, 314
houses see dwellings
Humboldt, Alexander von 7, 82
Humboldt current 36
humidity 31,38
Hunter, John 157
'hunting' phenomenon (finger temperature) 286
HVR see hypoxic ventilatory response (HVR)
hydralazine 239
hydration and dehydration 99
hydrocortisone 292
hydrogen ion concentration 59, 61, 62-3, 63, 109, 141
hydrostatic pressures 23
5-hydroxytryptamine 53
hyperbaria 229, 315
hyperbaric chamber/bag, portable 240,249
hypercapnia 52
hypercapnic ventilatory responses (HCVR) 50, 58, 59, 165
mechanism for resetting 59-60
hyperemia and frostbite 317
hyperhidrosis 317
hyperhydration 227
hyperosmolality 118
hyperoxia 73
hyperplasia 208, 211
hypersensitivity (cold) following trauma and exposure 321
hypertension 210-11
pulmonary see pulmonary hypertension
systemic 89, 324
hyperthermia 271
hyperthyroidism 213
hypertrophy, right ventricular 81
hyperventilation 62, 142
acid-base status of blood 109
alveolar gas composition 147
brain oxygenation 195
heat loss by 151
increase in oxygen affinity 107
hypobaric chamber 63

Index 427
hypocalcemia 291
hypocapnia 224
hypoglycemia 291, 303, 326
hypotension 193, 291,315
hypothalamic-pituitary-thyroid axis 186-7
hypothermia 271, 283, 294-5
acute/subacute/chronic 296
after drop 304
associated therapy 303
in avalanche 319
classification 295-6
clinical features 298, 299
complications 304, 305
death 298, 300
definition 295
exhaustion 297-8
frostbite 313
hemorrhagic hypovolemia 315-16
historical background 294-5
in hospital 300-1
and immune response 289
intravascular fluid volume 304-5
irrigation of body cavities 302, 302-3
management 299-300, 313
mild 298, 299
oxygen 303
pathophysiology 296-8
resuscitation methods 299, 300, 303
rewarming 298, 299, 300, 301-2, 303-4
severe 298-9, 300
ventricular fibrillation in 298, 300, 302, 304
see also cold injury; frostbite
hypothyroidism 213
hypoventilation
and HAPE 245
relative 57
hypoxemia 52, 65, 79
and abnormal heart rhythm 88
and exercise ventilation 134
and myocardial contractility 88
severe arterial 156-7, 164-5, 193
hypoxia 22, 43
abnormal heart rhythm 88
acclimatization and adaptation 45, 62
acute
and adrenosympathetic system 185-6
and control of blood glucose 187
adaptation over generations 209
arterial oxygen saturation 209
hypoxic pulmonary pressor response 209
antidiuretic hormone 179
avoidance during anesthesia 268
beta-adrenergic receptors 86
causing reduction in CSF bicarbonate concentration 60-1
central nervous system 191-201
cerebral tissue hypoxia and lactacidosis 62
chronic
and adrenosympathetic system 185-6
and control of blood glucose 187-8
and intermittent 49, 58
clinical lessons from high altitude 350
and the cornea 266
detraining of athletes 347-8
effect on acclimatized person 45
erythropoiesis 98-9
general deterioration 46
and heart rate 85, 87

hypoxic pulmonary pressor response 46, 209

increase in cardiac output 82
intracellular enzymes 127
isocapnia 54
mechanisms of action 192-5
cerebral blood flow 193-5, 224
nerve cells 192-3
myocardial 87
physiological response to 44-5
poikilocapnic 54
in porters 40
postsurgical myopic patient 267
pulmonary hypertension 89-91
severe tissue hypoxia during exercise 84
sleep state 160,160
symptoms of acute 45
systemic blood pressure 89
thyroid function 187
transduction of hypoxic response 52
vascular permeability and inflammation 245
vasoconstrictor response to 90
see also central nervous system; hypoxemia; hypoxic
ventilatory response (HVR)
hypoxic pulmonary pressor response 209
hypoxic ventilatory response (HVR) 49, 50-1, 53-5, 57, 148
acclimatization 53-4
acute mountain sickness (AMS) 55-6, 219
altitude performance 56-7
altitude residents 55, 207
blunting 55, 57, 119, 164
in chronic mountain sickness (CMS) 257
erythropoiesis 98-9
highlanders at sea level 55
lowlanders at high altitude 55
methods for measuring 53
residual impairment of CNS function 200
sleep 57, 156, 165, 165
variability 53
see also carotid body
ibuprofen 229, 315
ICAO standard atmosphere 25, 26
ice crystal formation in frostbite 312
ideal gas law 25
igloos 282
Iloprost 315
imidazopyridine 167
immigration into Tibet 35
immune response in athletes at altitude 348-9
immunosuppression in cold exposure 289
Inca civilization 35
indigenous high altitude dwellers 20-1
inducible nitric oxide synthase 102
infantile subacute mountain sickness 253
infants 205, 332-3
infection at high altitude 211-12
and pulmonary edema 238, 246
inflammation and HAPE 245
infrared analyzer 69
insulin 178, 188, 326
International High Altitude Expedition (Chile 1935) 82, 108, 112,
113, 117
central nervous system function 196, 200
exercise findings 131, 136-7
interstitial lung disease 325, 353-4
interstitium in pulmonary capillary 68
intestinal function see nutrition and intestinal function

428 Index
intracellular mechanisms 48
intracranial pressure and AMS 224-5
intravascular changes in extreme cold 287
Inuit people 285, 287
iodine deficiency 187, 212-13
ion absorption, intestinal 102
ion transport, defective transepithelial 246
ionizing radiation 32
ionosphere 25
iron 98, 104, 176
irrationality 248
irrigation 39
of body cavities for hypothermia 302
irritability 46
ischemia
in frostbite 310, 318
myocardial 89, 210, 259, 287, 354
transient cerebral 192
transient ischemic attacks 260
isocapnia 5
isocitrate dehydrogenase 129
isoflurane 269
isolation of people 39
Jesuit priest-travellers 5-7
joints and reaction to extreme cold 286, 327
Kangchenjunga, Mount 56
Karakoram range 34, 36, 46, 67, 143, 181
ketamine 269-70
kidney
and bicarbonate concentration 60, 116, 118
erythropoiesis in 102
general function and proteinuria 190
juxtaglomerular apparatus 99
microvascular permeability 226
sodium excretion and ANP 183
see also renal system
kinetic theory of gases 24, 25
Kirghizstan 80
Kollsman aneroid barometer 29
Krebs cycle (citric acid) 127-8,128
Krebs-Ringer bicarbonate 93
Kunlun mountains (China) 34, 37, 165
L-rhamnose 174-5
laboratories in the field 19-20, 360-1
accommodation 360
electrical supply 360-1
water, reagents etc. 361
lactacidosis 62, 63
lactate dehydrogenase 102, 129
lactate levels in blood 131, 136, 141, 149-50
lactate paradox 131-2, 141
lactic acid 49, 61, 62, 108, 109, 122
lactulose, urinary 174
Lake Louise AMS score 230, 231
Lake Louise Hypoxia Symposium (1991) 231
laminin 94
Laplace's law 244
latitude 25, 27,28
and lapse rate of temperature 30-1
tropical 42
and variation of barometric pressure 26-7
Lauricocha (Peru) 35
leakage, arterial 244
left ventricular failure in HAPE 241

leprosy 209, 212

leptin 168,171,^71, 226
lethargy see fatigue
leukotriene 225, 226,243
LH see luteinizing hormone
Lhasa (Tibet) 29, 35, 38, 42, 209-10
Lhotse Shar mountain 124, 129, 141
life expectancy 42
Lima (Peru) 36, 84, 112,127
limitation at extreme altitude 142-5
concept of 152-3
oxygen uptake on Everest summit 153-5
sixteenth to nineteenth centuries 143
twentieth century 143-4
livedo reticularis 321
liver enlargement 253
liver glycogen synthesis 188
llama 38, 46, 73, 74, 97, 110, 209
load-carrying 39-40, 40
loperamide 326
low pressure chambers 25, 26
lowlanders and acclimatization 64
lung
anatomy 67-8
development and function at high altitude 206
fluid loss 31
secretion ability 66
size and diffusing capacities 76
see also high altitude pulmonary edema (HAPE); p. artery
pressure; p. diffusion; p. emboli; p. hypertension; p.
stretch receptor stimulation; p. vascular resistance
lung disease
at altitude 325, 353
in chronic mountain sickness (CMS) 256-7
and polycythemia 256
lupus erythematosus and sunburn 292
luteinizing hormone (LH) 189
McKinley, Mount (Alaska) 28, 30
magnetic resonance imaging (MRI), changes in brain 199
magnetic resonance spectroscopy 63
malabsorption of small gut 46
malaria 211
malate dehydrogenase 129
malnutrition 277, 283
Massachusetts Institute of Technology expedition to Everest
(1998)29
mast cell density 93
Mauna Kea, Hawaii 195-6, 340
maximal voluntary ventilation (MW) 134
maximum oxygen intake 45, 85, 132, 137-9
and exercise 139-41, 153-5
medical check-up and risk factor 324
medroxyprogesterone acetate 255
membrane depolarization 52
membrane polarization 193
memory impairment 196, 198, 199-200
menarche and menstruation 206, 276, 330
menopause 277
mental performance 56, 57, 196-200,230, 328
clinical lessons from high altitude 353
and COLD 353
in extreme cold 289-90
and HAPE 235
outlook at altitude 328
see also brain
metabolism 41, 43, 48, 127

Index 429
basic metabolic rate (BMR) 169, 178
blockers 52
and clothing 281
compensation for respiratory alkalosis 108, 113-14, 116, 118
and heat injury 290
leucine 175
neurotransmitter 193
oxidative 129
protein 174, 175
response to cold 285, 289
see also thermal balance and regulation, physiological
mechanisms
methylpropionic acid 139
microclimates with houses and clothing 41
microvacuolation of neuronal perikaryon 193
microvascular permeability and AMS 225-6
migraine with ophthalmoplegia 260
migration 42
mining at high altitude 38, 39, 42, 132, 196, 340
built-in community 337-8
commuting pattern 338-40
history 336-7
mitochondria 65, 81, 119
density increase 121
and intracellular enzymes 128
oxidative phosphorylation 52
volume 125-6
mitral stenosis 94
Moguls 5
molecular biology of responses of pulmonary blood vessels 93
Monge's disease see chronic mountain sickness
monsoon, Asian 35, 36
Montana, Francisco 4
Monte Rosa see Capanna Regina Margherita
Montgolfier brothers 10
see also balloonists
Morococha (Peru) 29, 75, 97, 112, 114, 116
mining community 337-8
myoglobin concentration 126
peripheral tissue changes 121
morphine 239
mosquitoes 211
Mount Washington (USA) 36
mountain sickness 23, 32, 37, 131
acute see acute mountain sickness (AMS)
chronic see chronic mountain sickness (CMS)
subacute infantile and adult 2523
mountaineer as athlete 346-7
mountaineers 42
mountaineers see explorers
mouth, tingling 45
MRI see magnetic resonance imaging
mRNA 93, 94
mules 39
muscle
capillaries around 122-3
enzymatic activity of 127,128
fiber size 125
and frostbite 312, 316 ,
loss of muscle mass 172-3
leucine metabolism 175
nitrogen content 126
reaction to extreme cold 286
shortening 123
(smooth) in pulmonary blood vessels 92-3
wasting of skeletal 75
see also capillaries, capillary density

MW see maximal voluntary ventilation

myocardial contractility 81, 87-8
myocardial infarction 210, 320
myocardial ischaemia 89, 210
myocardium 88-9, 121, 126
myoepithelial cells 174
myoglobin 119, 120, 121, 126-7
myoglobulinuria 291
myopia, surgery for 266-7
myxedema 213
NADH and NADPH-cytochrome c-reductase 129
NADH-oxidase 129
NAD[P] + transhydrogenase 129
nasal problems 327
nasopharynx 288
natriuresis 102
nausea 217, 248
nedocromil 268
Nepal 13, 42, 104, 170, 185
nerve cells and hypoxia 1923
nerves
and frostbite 312
reaction to extreme cold 286
neurological problems at altitude 328
neuropsychological function see central nervous system
neurotransmitters 52, 193
neurovascular disorders 25961
New Guinea 34
New Zealand 34
nifedipine 228-9, 238, 239, 240, 244
nitric oxide 92, 102,245
and cerebral edema 251
inhibitors of nitric oxide synthesis 92
nitric oxide in treatment of RAPE 238-9
nitrogen content of muscle 126
nitroprusside 92
nitrous oxide as anesthetic 268
nitrovasodilators 92
NOAA25
nomad population 42
norepinephrine (noradrenaline) 53, 86, 185-6, 288
normocapnia 60
normoxia 46, 58, 60, 63, 93
North America, CMS in 256
NOVA expedition to Everest (1997) 29
NREM see sleep, changes of sleep state
numbness in feet (frostbite) 317
nutrition and intestinal function
body composition and weight loss 172-4
diet 175-7
energy balance at altitude 169-70
intestinal permeability 174-5,175
nutrition and metabolism in high altitude natives 177
protein metabolism at altitude 175
summary 168-9
weight loss on altitude expeditions 170-2
17-OHCS activity 288
o-methyltransferase 186
obesity and altitude 219, 327
occlusive intimal fibrosis 93
ointments for face protection 315
oliguria 253
ophthalmoplegia with migraine 260
oroya fever 211

430 Index
orthopedic conditions at altitude 327
see also bones and joints in frostbite
orthopnea 234
oscillatory behavior in control system 164
oxidative metabolism 129
oxidative phosphorylation 52
oxygen
and acute mountain sickness 220, 229
animals in oxygen-deprived environments 111
arterial oxygen saturation, and AMS 220
carrying capacity increase 98, 98, 105
concentration in dry air 30
cost of ventilation 151-2
diffusion
and exercise 135,137-9
and myoglobin 121
and perfusion limitation of transfer 72-3
diffusion limitation of oxygen transfer 76-9
dissociation curve 48, 51, 70, 73, 74,109, 114
on Everest summit 154
history 107-8
in hypothermia 303
enrichment of room air
during sleep 167
and neuropsychological function 2001
to relieve hypoxia 341-4
in fetus 80
hemoglobin-oxygen affinity (P50) 107, 108, 109-16
acclimatized lowlanders 113-14
and diffusion limitation 73-4, 115, 139
in high altitude natives 111-13
physiological effects of changes in 114-16
hemoglobinopathies with altered oxygen affinity 355
maximal consumption 132, 146
reaction rates with hemoglobin 69-70
saturation 76-8, 78, 165, 209, 219
secretion theory of lung diffusion 12-13, 66-7
and stroke volume 88
supplementary 22, 27, 28, 30, 46, 57, 67, 132, 142
maximum height without 155
transport system 46-8, 47
as treatment for RAPE 238
uptake
along pulmonary capillary 70-2, 71
and barometric pressure 146
and work rate 140-1,141
see also hemoglobin; hemoglobin concentration; hypoxia;
maximum expiratory flow of oxygen; mitochondria;
partial pressure of oxygen; pulmonary diffusion
oxyhemoglobin 70
Oxylog and electronic spirometers 362
-P50 see oxygen, hemoglobin-oxygen affinity
Pacific Ocean 35
packed cell volume (PCV) 98, 254, 258
palpitations, cardiac 82
Pamir range 33, 34, 104
papilledema 248
paracetamol 229
paresthesia in hands and feet 227
partial pressure of carbon dioxide 50, 51, 59-60, 109
in acute mountain sickness 224
alveolar 57-8
partial pressure of gases and high altitude physiology 355
partial pressure of oxygen 47, 52, 70-2,122,145
alveolar to arterial 47-8, 79
ambient to inspired 47

arterial 30, 51, 165

arterial to mixed venous 48
inspired 30, 51,57-8, 163
inspired to alveolar 47
reduced 45-6
time course for 70-2, 71
venous blood 151
Pascal, Blaise 23
pastoralism, nomadic 38, 39
patent ductus arteriosus 210, 325, 354
PD see potential difference across blood-brain barrier
PDGF see platelet-derived growth factor
pegorgotein 315
penicillin 211, 248
peptic ulcer 326
peptides, enkephalin-like 53
perfusion limitation of oxygen transfer 72-4, 72
peripheral edema 217,230, 352
peritoneal lavage 302
peritoneum and hypothermia 302
permeability
intestinal 174-5
microvascular (and AMS) 225-6
persistent cognitive impairment 199
personnel management of mountaineering 359
Peru see Andes (South America); Lima (Peru)
pH 51, 60-1, 62
arterial 74, 107, 116-18,136
brain intracellular 63
Henderson-Hasselbach equation 116
lack of stability in CSF 63
phenothiazines 292
phentolamine 239, 240, 245
phlebitis of limbs 260
phosphofructokinase 102, 129, 150
photophthalmia see snow blindness
physiology of extreme altitude 145-52
acid-base status 149-50
alveolar gas composition 147-8
barometric pressure 146-7
cardiac output 150
heat loss by hyperventilation 151
oxygen cost of ventilation 1512
partial pressure of oxygen 151
pulmonary diffusing capacity 1501
physiology (high altitude), contribution to clinical medicine
355-6
Pikes Peak expedition (Colorado 1911) 24,29,66,82,84, 131,
194
pituitary gland 186-7
placenta 80, 204
plasma aldosterone concentration (PAC) see aldosterone
plasma arginine vasopressin (AVP) 118
plasma endothelin levels see endothelin
plasma potassium concentration 61
plasma renin activity (PRA) see renin-angiotensin-aldosterone
system, renin activity
plasma volume 45, 49, 98, 99-102,100
effect of altitude on 101-2,102
and exercise 100,101
measurement methods 101
posture and 100
regulation of 99-100, 99
platelet-derived growth factor (PDGF) 93
platelets
adhesiveness 262
and clotting 261-2

Index 431
counts at altitude 262
plethysmograph, inductance 162
pneumonia 232-3
polar hands (in frostbite) 316-17
pollution and tourism 39
polycythemia 65, 73, 81, 85, 87
and cerebral blood flow 195, 258
and chronic mountain sickness (CMS) 154, 254, 256, 258
of high altitude 103, 105, 106, 182
and increased hematocrit 256, 347
and lung disease 256, 354
and proteinuria 190
polyethylene glycol 315
population at high altitude 36, 39, 42-3, 202-3
adaptation to cold 209
adaptation to hypoxia over generations 209
age and sex distribution 203
arterial oxygen saturation 209
atherosclerosis 210
birth defects 210
birth weight and infant mortality 205
cardiovascular adaptations 208
carotid body and chemodectoma 208
congenital heart disease 210
demographic aspects 203-4
dental conditions 214
diseases 209-10
fertility 203-4
fetal and childhood development 204-6
goiter 212-13
growth through childhood 205-6
hemoglobin concentration 207-8
hypertension 210-11
hypoxic pulmonary pressor response 209
infection 211-12
mortality 203
physiology 206-9
pregnancy 204-5
sickle cell disease 214
stature, lung development and function 206
ventilatory control at rest and exercise 207
porphyria and sunburn 292
porters 39-40
posture and plasma volume 100
potassium 52, 291
potassium ion channels 92
potential difference (PD) across blood-brain barrier 61
PRA see renin-angiotensin-aldosterone system, renin activity
and altitude
pregnancy 204-5, 276, 331
priest-explorers 507
Priestley, J. G. 25-6, 67
procollagen 93, 94
prostacyclin 315
prostaglandins 92
protein 174, 175
proteinuria 190,190, 226, 236
proton secretion 118
psychological approach see mental performance
pulmonary arterial pressure experiments (cats) 89-90, 90
pulmonary arterioles 92, 93
pulmonary artery pressure 89, 90-3, 136
experiments on cats 89-90
reaction to extreme cold 287
in response to hypoxia 219-20
pulmonary capillaries see capillaries, pulmonary
pulmonary diffusion 65-7

capacity at high altitude 74-6, 75, 77, 115, 150-1

acclimatized lowlanders 745
high altitude natives 75-6
Pick's law of diffusion 68-9
history 66-7
limitation 72-3, 79
and oxygen affinity of hemoglobin 73-4
and lung size 75
measurement of capacity
by single breath method at rest 74
exercising subjects 75
measurement of diffusing capacity 69
physiology 6774
in placenta 80
reaction rates with hemoglobin 6970
pulmonary edema
high altitude (HAPE) see high altitude pulmonary edema
high permeability type 92
neurogenic 246
subclinical 78, 136
pulmonary emboli, multiple 245
pulmonary hypertension 81, 82, 87, 89-91, 92-3
in high altitude pulmonary edema 240, 242
right ventricular hypertrophy 95
pulmonary stretch receptor stimulation 163
pulse oximetry 362
pulse pressure 89
pulse rate 82
puna see acute mountain sickness (AMS)
PV see plasma volume
Pyrenees (between Spain and France) 33
pyruvicacid 61
Qomolangma (Himalayas) 95
Quechua Indians 205
rabies 209
radial keratotomy for myopia 259
radiation
in thermal exchange 274-5
see also cosmic radiation; ionizing radiation; solar radiation;
ultraviolet radiation
radioimmunoassays and EPO estimation 102
radiosonde balloons 27, 28
rainfall 36-7
rapid eye movement see sleep, paradoxical or REM; sleep, slow
wave
Raynaud's disease/phenomenon 320
RCM see blood, red cell mass
rectus palsy 260, 261
red cell mass see blood, red cell mass (RCM)
reduced partial pressure of oxygen 45-6
reinfusion of blood (doping) 106
REM see sleep, rapid eye movement
remodeling, vascular 81
Renaissance 23
renal failure 291,317
renal function at altitude 178-9, 190
renal perfusion, decreased 291
renal system 178-9
effective renal plasma flow 190
urine in high altitude pulmonary edema 236
renin-angiotensin-aldosterone system 99, 101, 180-3,180
aldosterone and altitude 180-1
control of aldosterone release 182
effect of altitude on aldosterone response to renin 182-3,
182

432 Index

renin-angiotensin-aldosterone system cont.

exercise and 178, 181-2
renin activity and altitude 181
research 20, 357-64
respiratory infections 212
respiratory measurements in the field 361-2
respiratory medicine and clinical lessons 356
respiratory quotient (RQ) 175-6,176
respiratory system
bubbling respirations 234
depressant drugs and HVR 53
physiology 26, 276
reaction to extreme cold 288
rest and symptoms of AMS 229
resuscitation methods 299, 300
resynthesis of muscle glycogen after depletion 46
reticulocyte counts 102
reticulocytosis 49
retinal hemorrhage 248, 260, 265-6
rewarming techniques for hypothermia 3014
rhabdomyolysis 291
rhythm, abnormal heart 88
Ringer's lactate solution 303
risk associated with medical conditions at altitude 322-8
Rocky Mountains (USA and Canada) 33
Royal Society/Chinese Academy of Sciences Tibet Geotraverse 35
RQ see respiratory quotient
Sajama, Mount 170, 174, 188
salametrol 268
sea level pressure and temperature 25
season and variation of barometric pressure 278,27,28, 29
selective reminding test 198
Sengstaken tube 303
serum cholesterol 210
serum immunoreactive EPO concentration (SiEp) 102-3,103
serum osmolality 31, 99, 180
serum potassium 303
serum sodium concentration 180
sex distribution see gender distribution
sheep, and hypoxic pulmonary vasoconstriction 92
shelter and thermal balance 282
Sherpas 40, 41, 55, 104, 113, 120
and adrenergic response 186
and basal metabolic rate 169
and control of breathing during sleep 163-4
nutrition and metabolism 177
and weight loss 171
shivering 41, 42, 264, 276, 283, 285
and hypothermia 297, 298, 301
short-wave radio propagation 25
shortness of breath see breathlessness
sickle cell disease/trait 214, 326
SIDS (sudden infant death syndrome) 333
SiEp see serum immunoreactive EPO concentration
Sierra Madre (Mexico) 33
Sierra Nevada range (USA) 33, 111
Sikiang (Tibet) 34
Silver Hut Expedition (1960-1) see Himalayan Scientific and
Mountaineering Expedition (1960-1)
Similaun Man 34
sinus arrythmia 88, 163
skiing (tourism) 39
skin
cancer and ultraviolet radiation 292-3
in frostbite 310
grafts for frostbite 315

and peripheral vessels in extreme cold 286

and subcutaneous tissue infections 106
sunburn 292
and thermal exchange 275-6
skis to facilitate movement 43
sleep
at altitude 230, 328
changes of sleep state 160
characteristics at high altitude 159-60
and chronic mountain sickness (CMS) 257
control of breathing 163-4
deprivation 159
effect of oxygen enrichment of room air 166
in field studies 362
field studies 362
four studies at 8050 m 88
and hypoxic ventilatory response (HVR) 57, 156, 164, 165
increased frequency of arousals 159
paradoxical or REM type 159
periodic breathing 157-8,158, 159, 160-7
characteristics 160-2,161,162
effects of drugs 166-7
gas exchange 165-6
mechanism 164-5
physiology 158-9
position during 41
quality 157, 160
rapid eye movement (REM) 160,160
sinus arrythmia 88,162
slow wave 159, 160
summary and history 156-7
thermoregulatory patterns 282-3
and ventilation 257
smallpox 209-10
smoking 219, 315, 318
snow blindness (photophthalmia) 41, 261, 291-2
snow and radiation 38
sodium cyanate 139
sodium retention 181-2, 184, 288
sodium status 99, 101
sodium and water balance in AMS 222-4
soil conditions 39
solar radiation 31, 36, 38, 211, 282
soroche see acute mountain sickness (AMS)
South America 3-5
spectacles see glasses, protective
spironolactone and acute mountain sickness 228
splinter hemorrhages 263
sports 131
see also athletes and altitude
square wave pulses of hypoxia 53
Starling equation 99, 100
stature of high altitude population 206
STDP (standard temperature and pressure, dry gas) 131, 133
storage of samples in field studies 363-4
stratosphere 25, 27
stress failure in pulmonary capillaries 242-4
stroke 259, 260
see also heat stroke
structural changes in hypoxic pulmonary vasoconstriction 91-5
succinate dehydrogenase 129
sulfur hexafluoride 73
sulfonamides 292
sumatriptan in acute mountain sickness 229
sun see solar radiation
sunburn 292
superoxide dismutase 315

Index 433
surfactant 68
sweating 275-6, 277-8
swimmers and HVR 53
sympathectomy for frostbite 315
tachycardia 100, 234, 253, 291
tachypnea234, 291
TB see tuberculosis, pulmonary
tectonics, plate 35
teeth see dental conditions
telescope sites 340-1
temazepam 166-7
temperature 30-1, 37-8
adaptation to cold 43
and 'after drop' 304
and apparent death 294, 298
in atmosphere 25
body temperature at extreme altitude 30, 36, 276-7
humidity 31,38
ionizing radiation 32
and oxygen affinity of hemoglobin 109-10
and solar radiation 31, 38
in tents and bivouacs 319
thermal balance 271-2
wind chill factor 31
see also BTPS and STPD; hypothermia; thermal balance and
regulation
Tenerife34, 108, 113, 158
Tensing, Sherpa 144
tents and bivouacs 319
see a Iso dwellings
terraces 39
terrain 36, 37
testosterone 189-90, 204
TGF see transforming growth factor
theophylline in acute mountain sickness 228
thermal balance and regulation 271-3
air insulation and wind chill 289
air movement 274
at high altitude 282
behavioral mechanisms 272
cold induced vasodilatation 273
conduction 275
convection 273, 274
core temperature 272
countercurrent heat exchange 278
evaporation 275-6
factors altering regulation 282-3
heat conservation 278-82
heat loss 277-8
heat production 277
insulation 278, 279-81
and oxygen consumption 281-2
physiological mechanisms 272
radiation 2745
respiratory tract 276
shelter 282
skin 275-6
thermal exchange 273-4
thermogenesis 277
tissue insulation 278-9
variation of body temperature 276-7
vasoconstrictioin 278
wind and wind chill 271-2, 279
see also hypothermia; thermal extremes
thermal extremes 284
reaction to cold 284-90

alimentary tract 288

cardiovascular system 286-8
in children 333
hormonal responses 288-9
immune response 289
mental function 289-90
metabolic response 285
nerves, muscles, joints 286
respiratory tract 288
skin and peripheral vessels 286
tolerance 285
see also cold injury, nonfreezing; frostbite; hypothermia
reaction to heat 290-3
in children 333
injury 290-1
skin cancer 292-3
solar radiation 291-2
response to cold, fatigue 289
thermogenesis 277
thiazide diuretics 292
thirst 31,287
thrombocytopenia 298
thrombophlebitis 260
thrombosis 103, 225, 250
in acute mountain sickness 225
coronary and cerebral 260, 263, 320
and frostbite 313
risk factors 263, 265
thyroid carcinoma 208
thyroid function 178, 186-7
in extreme cold 289
see also goiter
TIA see transient ischemic attacks
Tibet 33, 34-5, 36, 37, 38, 39, 43
chronic mountain sickness 255-6
economics 38-9
hemoglobin concentration 104, 105
HVR and altitude residents 55
polycythemia 105
population 42
traditional medicine 209-10
see also Lhasa (Tibet)
time course for partial pressure of oxygen in pulmonary capillary
70-2
tingling of fingers and mouth 45
tissue change
caused by training 125
diffusion in, principles 121-2
peripheral 120, 137-9
diffusion in 121-9
tissue partial pressures 122-3
tobacco see smoking
tourism 39
trade at altitude see commerce at altitude
trade and population 43
training at altitude for athletics 346
transepithelial ion transport, defective 246
transforming growth factor (TGF) 93, 94
transient ischemic attacks (TIA) 260, 261
'trench foot' 317, 318
triiodothyronine 1878
tropopause 25, 27
troposphere 25, 26
tuberculosis, pulmonary 212
tubular necrosis 291
turbine flow meter 135
Turkey 33

434 Index

tutek see acute mountain sickness (AMS)

typhus 211
ulcerative colitis 326
ultraviolet radiation 38, 292-3
urine see kidney; renal system
USA see North America
vacuum 23
valleys and population, mountain 36
Vallot observatory (France) 29, 101
valve replacements 324
vaporizers in anesthesia at altitude 269
vascular accidents 263-5
vascular capacity 99
vascular endothelial growth factor 102
vascular permeability 245
vascular remodeling 94
vasoconstriction 91-2, 278, 297, 318
peripheral 99, 297
posture and plasma volume 100
pulmonary 82, 90, 92, 135, 151
mechanism and site 91
(uneven) and perfusion 242
vasodilatation 273, 277, 318
peripheral 42, 99, 286
vasodilators in treatment 238-9, 315
vasomotor control and core temperature 272
vasopressin 223, 227
venepuncture in field studies 363
venereal disease 209
venesection 253, 265
Venezuela 35
ventilation
and anesthesia 268
blunting of HVR see hypoxic ventilatory response
carbon dioxide response 64,163, 268
carbon dioxide ventilatory response and acclimatization 58
classical measurement methods 361-2
control at rest and exercise in high altitude 207
critical 152
during sleep 163, 257
effect of acute hypoxia on 51
and exercise 130, 133-5
levels 31,44, 45, 51
maximal voluntary 134,134
minute 51
oxygen cost of 151-2,152
three chemical drives 51
ventilation-perfusion inequality 78-9, 79, 92
see also carotid body; gases, alveolar; hypercapnic ventilatory
responses (HCVR); hypoxic ventilatory response (HVR);
normoxia
ventilation/perfusion relationships 135-6
ventricles (brain) 61, 62, 63
ventricular ejection fraction 88
ventricular failure 235, 241
ventricular fibrillation 298, 300, 302, 304

ventricular hypertrophy, right 95, 208

ventricular septal defect repair 324
ventricular/atrial contractions, premature 81, 88
venular constriction and HAPE 244
vicuna 73, 74, 110
viruses 211
viscosity of blood, increased 103, 105
vision (night) 45
see also eye conditions
vitamins in diet 98, 175
volume depletion, chronic 31
vomiting 217, 248
water vapor pressure 30, 31
weather prediction 24
Wechsler memory scale 198
weight and infant mortality, birth 205
weight loss 46, 166, 168-9
at altitude 170-4, 171-2,171
and body composition 172-3
in chamber experiments 172
on march out 170
and prolonged cold 287
in women 171-2,330-1
White Mountain summit (California) 29
Whymper, Edward 9-10, 143
Wilcoxon signed-rank tests for CNS 199
willpower, lack of 46
wind and wind chill 31, 36, 38, 273-4, 296
effect on clothing 281
women
acrocyanosis 320
diffusion in placenta 80
and high incidence of goiter 213
and iron intake 176
menarche and menstruation 206, 276, 330
menopause 277
pregnancy 204-5, 276, 331
response to altitude 329, 330-1
systemic hypertension 89
thermoregulatory response 276
and weight loss 171-2, 330-1
see also children; fetus; gender; infants
work at altitude see commerce at altitude
World Congress on Mountain Medicine (1998) 256
World War I 306, 318
World War II 26, 295, 306
Xinjiang (Chinese Turkestan) 34
yaks 30, 38, 40, 46, 209
yellow fever 211
yeti stories 7-8
yoga, g-tum-mo 42, 43, 285
zolpidem 167
zona occludens 174